Small molecule potentiators of metabotropic glutamate receptors

ABSTRACT

The present invention relates to small molecule potentiators of metabotropic receptors, in particular of the mGlu2 receptor. The present invention also relates to the use of these compounds for the prevention or treatment of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The present invention thus provides compounds of formula I 
                         
wherein X 1  is N or C—R 1 , X 2  is N or C—R 2 , X 3  is N or C—R 3 , X 4  is N or C—R 4  provided that none or one of X 1 , X 2 , X 3  or X 4  is N; Y 1  is N, C or C—R 5 , Y 2  is N, C or C—R 6 , Y 3  is Y 1 , Y 2 , N, C or C—R 7 , Y 4  is N, C or C—R 8  provided that only the moiety Y 1 , Y 2 , Y 3  or Y 4  to which Z is bound is C and further provided at most one of Y 1 , Y 2 , Y 3  or Y 4  is N; Z is O, S, S(O), S(O) 2  or NR Z ; Q is CH 2  or CH 2 CH 2 , where one or two of the hydrogen atoms in CH 2  or CH 2 CH 2  may be replaced by halogen, C 1 -C 4 -alkyl or C 1 -C 4 -haloalkyl; R 1  is inter alia hydrogen, halogen, C 1 -C 6 -alkyl, C 1 -C 6 -haloalkyl, C 1 -C 6 -alkoxy, C 1 -C 4 -haloalkoxy, C 3 -C 8 -cycloalkyl, a radical NR 1a R 1b , C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ring members, aryl, aryl-CH 2 , aryloxy, hetaryl, hetaryloxy or hetaryl-CH 2 , wherein the heterocyclyl, aryl and hetaryl rings ring in the last six radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical or different radicals R 1c ; R 2  has one of the meanings given for R 1 ; R 3  and R 4  are, inter alia, selected from hydrogen, halogen, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 3 -C 6 -cycloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, phenyl, C 1 -C 4 -haloalkoxy, a radical (CH 2 ) n NR′R″; R 5 , R 6 , R 7 , R 8  are, independently of each other, selected from hydrogen, halogen, etc.; R a  is C 3 -C 6 -cycloalkyl, C 1 -C 6 -haloalkyl or C 1 -C 6 -alkyl, which is unsubstituted or carries one radical selected from C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy and a radical NR a1 R a2 ; and the N-oxides and the pharmaceutically acceptable salts thereof.

CROSS-REFERENCE TO RELATED APPLICATION

This is the non-provisional of U.S. Provisional Patent Application No.61/319,065, filed on Mar. 30, 2010, the contents of which are herebyincorporated by reference.

The present invention relates to small molecule potentiators ofmetabotropic receptors, in particular of the mGlu2 receptor. The presentinvention also relates to the use of these compounds for the preventionor treatment of neurological and psychiatric disorders associated withglutamate dysfunction and diseases in which metabotropic glutamatereceptors are involved.

BACKGROUND OF THE INVENTION

Glutamate, the major excitatory neurotransmitter in the brain, elicitsits effects by activating ligand-gated cation channels, termedionotropic glutamate receptors (iGluRs), as well as metabotropicglutamate receptors (mGlu receptors). The latter belong to the G-Proteincoupled receptor (GPCR) family 3 (Conn and Pin, Annu. Rev. Pharmacol.Toxicol. 37, 205-37, 1997) and are coupled through heterotrimericG-proteins to intracellular effector systems. These receptor types exertmultiple modulatory effects within the central nervous system (CNS).Eight mGlu receptor subtypes have been cloned from mammalian brain todate. Depending on their G-protein coupling profile, pharmacology andsequence identity, these receptors are classified into three groups(Conn and Pin, Annu. Rev. Pharmacol. Toxicol. 37, 205-37, 1997). Group ImGlu receptors primarily couple through Gq to increases inphosphoinositide hydrolysis and the cellular Ca²⁺-system viaphospholipase C (PLC), and include the mGlu1 receptor and mGlu5receptor. Group II mGlu receptors, which include mGlu2 and mGlu3,inhibit adenylylcyclase (AC), just as group III mGlu receptors, whichcomprise mGlu4, mGlu6, mGlu7 and mGlu8. Thereby, in groups II and III,the pertussis-toxin sensitive G-protein Gi is involved in signaltransduction. However, group II and group III mGlu receptors differ intheir sequence identity and pharmacological profile.

Of the 8 mGlu receptor subtypes various splice variants exist. Withingroup I mGlu receptors the splicing variability is most pronounced. MGlu1 exists in 6 different splicing forms. The receptors mGlu1a/a, 1b/b,1c, 1d and 1f all differ in their C-terminal, intracellular domain(Prezeau et al., Mol. Pharmacol. 49, 422-429, 1996; Soloviev et al.,Biochimica et Biophysica Acta 1446, 161-166, 1999), and mGlu1e istruncated N-terminally, lacking most of the protein coding region (Pinand Duvoisin, Neuropharmacol. 34, 1-26, 1995). So far of mGlu5 (groupI), and the group III receptors mGlu4, mGlu7 and mGlu8 two splicingvariants have been demonstrated. mGlu6, which is located solely inON-bipolar cells of the retina (Nakanishi et al., Brain Res. Rev. 26,230-235, 1998), only has one isoform. The same holds for mGlu2 and mGlu3receptors (Fagni et al., TINS 23 (2), 80-88, 2000).

The synaptic localization of group I mGlu receptors and group II/IIImGlu receptors differs. While group I receptors are locatedpredominantly postsynaptically, group III mGlu receptors rather show apresynaptic localization (Shigemoto et al., J. Neurosci. 17, 7503-7522,1997; Cartmell & Schoepp, J. Neurochem. 75(3), 889-907, 2000). Group IIreceptors seem to be located pre- and postsynaptically, depending onbrain region and synapse-type. A perisynaptic localization of mGlu2 hasalso been demonstrated. In this case the receptor might only beactivated under high frequency stimulation, then preventing furthertransmitter release and thus reducing pathologically high levels ofglutamate within the synaptic cleft. Autoreceptor function (medialperforant path, mossy fiber-CA3, spinal cord synapse, corticostriatalsynapse) and heteroreceptor functions have been demonstrated for groupII mGlu receptors at synapses in diverse brain regions. The pre- andperisynaptic localization of group II mGlu receptors, combined withtheir auto- and heteroreceptor function and their coupling to inhibitoryintracellular signalling cascades implies an important role of thisreceptor type for the regulation of excitatory neurotransmission.

The first compounds which discriminated between the 3 different groupsof mGlu receptors were low affinity agonists: 3,5-dihydroxyphenylglycine(3,4-DHPG), which selectively stimulates the group 1 mGlu receptors;(2R,4R)-4-aminopyrrolidine-carboxylic acid (2R,4R-APDC) activating groupII mGlu receptors (Monn et al., J. Med. Chem. 39(15), 2990-3000, 1996)and L-Amino-4-phosphonobutyrate (L-AP4, Trombley and Westbrook, J.Neurosci. 12(6), 2043-50, 1992) for the activation of group III mGlureceptors. All these compounds have been valuable tools for theinvestigation of the various functions of mGlu receptors by in vitrostudies, but none of these compounds has been shown to exert potentcentral effects after systemic administration. Other early compounds,which have mainly been used for in vitro studies, turned out to activateionotropic glutamate receptors as well. For the widely used group IImGlu receptor agonist (2S,1′R,2′R,3′R)-2-(2′,3′-dicarboxypropyl)glycinealso activates NMDA receptors.

For studying the in vivo effects and therapeutic applications of groupII agonists, the breakthrough came from the discovery of LY354740 andLY379268 (Formulae given e.g. in D. A. Barda et al., Bioorganic andMedicinal Chemistry Letters, 14, 3099-3102, 2004). These two compoundsare highly specific group II receptor agonists with only very lowaffinity to other mGlu receptors or ionotropic glutamate receptors. Theyhave EC₅₀ values of 10 and 20 nM (LY354740) and 3 and 5 nM (LY379268),for mGlu2 and 3 respectively. While a differentiation between the twogroup II receptors is not possible, a specificity of >1:30.000 towardsgroup I receptors and between 1:100 (mGlu6) to >1:30.000 (mGlu7) togroup III receptors offers a high discrimination potential to thesereceptor types (Cartmell and Schoepp, J. Neurochem. 75(3), 889-907,2000; Brauner-Osborne et al., J. Med. Chem. 43 (14), 2609-2645, 2000).Both compounds were designed as conformationally constrained analoguesof glutamate (Monn et al., J. Med. Chem. 40(4), 528-37, 1997; J. Med.Chem. 42(6), 1027-40, 1999), and represent competitive agonists at theglutamate binding site. Furthermore these two compounds are systemicallyactive.

Derivatives of these compounds, MGS 0008 and MGS 0028 (Nakazato et al.,J. Med. Chem. 43(25), 4893-909, 2000) and have a higher oralavailability. They also show increased antagonistic effects onPCP-induced head-weaving and hyperactivity in rats. Recently also ahighly selective antagonist for group II mGlu receptors has beenidentified (Kingston et al., Neuropharmacology 37(1), 1-12, 1998;Johnson et al., Neuropharmacology 38(10), 1519-29, 1999). No appreciablespecific binding of the radio-ligand [3H]-LY341495 (formula given in D.A. Barda et al. 2004) was found in membranes of cells expressing humanmGlu1a, mGlu5a, mGlu4a, mGlu6, or mGlu1a receptors. Many effects inducedby group II receptor agonists could be reversed by this compound. ThusLY341495 also represents a highly selective tool compound.

Positive modulators activate the mGlu2 receptor dependent on thepresence of glutamate (potentiators). Thus, the compound “sensitizes”the receptor to react already at lower concentrations of the ligand.Positive modulators can also activate the mGlu2 receptor directly. ThemGlu receptors consist of a large extracellular N-terminal domain, whichbinds the natural ligand, glutamate, which is homologous to theperiplasmatic amino acid binding proteins from bacteria. This domain islinked to a 7-transmembrane domain. This canonical domain, common to allG-protein coupled receptors, contains the canonical ligand binding sitefor GPCRs (compare rhodopsin in retinal). In the mGluRs this site isfree and may play a role as modulatory site for positive and negativeallosteric compounds.

A hint for the exact amino acid sites responsible for ligand binding ofa model potentiator (LY487379, see Johnson et al., J. Med. Chem. 46(15),3189-92, 2003) come from the amino acid comparison between mGlu2receptor and mGluR3 in this region. As the potentiator is specific formGlu2 receptor, the binding should not take place at mGluR3 and theresponsible amino acids should be exactly the ones which differ betweenthe two receptors. Recently the binding site of a model potentiator(LY487379) has been mapped by site directed mutagenesis. The bindingsite seems to be within the transmembrane domain of mGlu2 receptor(Schaffhauser et al., Mol. Pharmacol. 64(4), 798-810, 2003). Inparticular the amino acids 688, 689 and 735 are indicated for binding.

MGlu2 receptor is expressed in both separate and overlapping circuits ofrelevance for neuropsychiatric and neurological disorders. This includesexpression in neocortex, thalamus, striatum, amygdala and hippocampus.Within these circuits mGlu2 receptor is mainly expressedpresynaptically. As a consequence of this expression pattern it has beenshown that excitatory transmitter release is regulated by group IIagonists in diverse brain regions. For, it has been demonstrated thatgroup II agonists normalize PCP-induced increase of glutamate in theprefrontal cortex (PFC) and that dopamine is regulated by group IIagonists in a region-specific manner. As one function group II agonistsincrease dopamine and metabolites in the PFC. Also serotonin andmetabolites are regulated in the PFC. This has further been demonstratedby a functional antagonism of 5-HT2A receptors in this brain region.

These data indicate that the mGlu2 receptor approach may normalize anumber of de-regulated transmitters in schizophrenia. The mGlu2 receptoragonist/potentiator concept will likely give rise to the opportunity tonormalize

-   -   positive symptoms, due to regulation of glutamate,    -   negative symptoms, due to regulation of dopamine and serotonin,        and    -   cognitive symptoms, due to regulation of acetylcholine in the        PFC.        Besides schizophrenia, drug abuse may be an interesting disease        indication, as group II agonists block of expression of        locomotor sensitization by amphetamine, among a multitude of        other described effects. The usefulness of such compounds is not        limited to the disease states described above.

The potentiator concept for mGlu2 receptor is relatively new (Barda etal., 2004), but necessary to evaluate the relevance of mGlu2 receptorversus mGluR3. This is of note, as the group II agonists described abovedo cross react with both receptor types. Within the recent year, reportsdirectly demonstrate the relevance of mGlu2 receptor in psychosis modelsin rodents by describing function of mGlu2 receptor potentiators inmodels of PCP-induced hyperlocomotion, amphetamine-inducedhyperlocomotion, and reversal of amphetamine-induced disruption of PPIin mice (Galici et al., JPET 315(3), 1181-1187, 2005).

Beyond these data, indicating a relevance of mGlu2 receptor potentiatorsin schizophrenia, new reports furthermore demonstrate efficacy of mGlu2receptor potentiators in anxiety, as potentiators have been shown to beefficacious in rat fear-potentiated startle and stress-inducedhyperthermia in mice (Johnson et al. Psychopharmacol., 179(1), 271-83,2005).

A pure NMDA activation approach (the “glutamatergic hypothesis ofschizophrenia”) may result in side effect liabilities. In particular,excitotoxicity is a relevant side effect which needs to be consideredearly within a potential screening cascade of such projects. This sideeffect liability may limit the usefulness of such approaches.

As described above, the mGlu2 receptor positive modulator approach doesnot purely rely on the glutamatergic hypothesis, but likely is involvedin the normalization of release of a number of excitatoryneurotransmitters. Consequently, to date there is no evidence forexcitotoxic liability of group II agonists or mGlu2 receptor positivemodulators. Group II agonists even show the opposite effects. They areneuroprotective in the MPTP model of Parkinson's disease, they reducelow Mg²⁺-induced epileptiform discharges in slice preparations and theyhave anticonvulsant action in acute seizure models.

As a relevant side effect, a negative influence on cognition wasdescribed for group II agonists (Higgins et al., Neuropharmacol. 46,907-917, 2004). However, to date this finding is controversial in theliterature. While one group finds a reversal of cognitive deficitsinduced by PCP (Moghaddam and Adams, Science 281(5381), 1349-52, 1998),a second group finds a reduction of DNMTP performance with the mGlu2receptor agonist LY354740, which is not present in mGlu2 receptorknockout mice (Higgins et al., Neuropharmacol. 46, 907-917, 2004). Thisfinding contrasts to the data from Moghaddam and Adams and would alsocontradict the normalization of ACh release in the PFC by this compound(see above).

WO 2006/015158 and WO 2006/047237 describe heterocyclic compoundscarrying an indanone moiety, the compounds being potentiators ofmetabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/030032 describes pyridinone compounds which are potentiators ofmetabotropic glutamate receptors, including the mGlu2 receptor.

WO 2006/049969 describes N-(phenyl)aminoalkyl substituted pyrimidinecompounds, which are potentiators of metabotropic glutamate receptors,including the mGlu2 receptor.

WO 2006/057860, WO 2006/057869 and WO 2006/057870 describe compoundscarrying a 4-acyl-3-hydroxy-phenyl moiety. The compounds are suggestedto be potentiators of metabotropic glutamate receptors, including themGlu2 receptor.

WO 2006/091496 describes compounds carrying a benzazole moiety, thecompounds being suggested as potentiators of metabotropic glutamatereceptors, including the mGlu2 receptor.

WO 2006/020879, WO2007/021308 and WO 2007/021309 disclose isoindolonecompounds, which are suggested as potentiators of metabotropic glutamatereceptors, including the mGlu2 receptor.

WO 2008/145616 discloses heterocyclic compounds which are positivemodulators of metabotropic receptors, including the mGlu2 receptor.

Although the compounds of prior art have a high affinity with regard tothe mGlu2 receptor, their receptor binding profile and/or theirpharmacological profile is not always satisfactory. In particular, thecompounds often have poor selectivity with regard to mGlu2 receptor incomparison with mGlu3 or group III mGlu receptors or are glutamateagonists. Moreover the potentiators are in terms of (i) bindingaffinity, (ii) receptor potentiation and/or stimulation profile, (iii)selectivity versus other receptors, (iv) physicochemical properties, (v)in vitro microsomal stability and (vi) pharmacokinetic parameters notsatisfactory.

It is an object of the present invention to provide further compoundswhich are potentiators of metabotropic glutamate receptors, inparticular of the mGlu2 receptor, and which thus are useful in thetreatment or prevention of neurological and psychiatric disordersassociated with glutamate dysfunction and diseases in which metabotropicglutamate receptors are involved. In particular, such diseases arecentral nervous system disorders selected from the group ofschizophrenia, drug abuse, anxiety, migraine, depression and epilepsyand the like.

These and further objects are solved by the compounds of the generalformula I, as described herein, as well as by the tautomers thereof, andby their pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION

The present invention thus provides compounds of formula I

-   -   wherein    -   X¹ is N or C—R¹    -   X² is N or C—R²    -   X³ is N or C—R³    -   X⁴ is N or C—R⁴    -   provided that none or one of X¹, X², X³ or X⁴ is N;    -   Y¹ is N, C or C—R⁵    -   Y² is N, C or C—R⁶    -   Y³ is N, C or C—R⁷    -   Y⁴ is N, C or C—R⁸    -   provided that only the moiety Y¹, Y², Y³ or Y⁴ to which Z is        bound is C and Y², further provided that 0, 1 or 2, preferably        at most one of Y¹, Y², Y³ or Y⁴ is N;    -   Z is a covalent bond, CR^(Za)R^(Zb), O, S, S(O), S(O)₂ or        NR^(Zc);        -   R^(Za), R^(Zb) are independently of each other selected from            hydrogen, halogen and C₁-C₄-alkyl;        -   R^(Zc) is hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, which is unsubstituted            or carries one radical selected from C₁-C₄-alkoxy and            NR^(Z1)R^(Z2);            -   where R^(Z1) and R^(Z2) are independently of each other                selected from hydrogen, C₃-C₆-cycloalkyl,                C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and                C₁-C₄-alkoxy-C₁-C₄-alkyl, or            -   R^(Z1) and R^(Z2) together with the nitrogen to which                they are attached form a 5- or 6-membered N-bound                saturated heterocycle, which, in addition to the                nitrogen atom may comprise a further heteroatom,                selected from O, S and N, as ring member and which is                unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl                radicals;        -   or R^(Zc) is a radical S(O)₂R^(Z3) or a radical            S(O)₂NR^(Z4)R^(Z5),            -   where R^(Z3) is C₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,                C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,                C₃-C₆-cycloalkylmethyl, phenyl or benzyl, wherein the                phenyl ring in the last two mentioned radicals itself is                unsubstituted or carries 1, 2, 3, 4 or 5 identical or                different radicals selected from halogen, C₁-C₄-alkyl,                C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,            -   R^(Z4) and R^(Z5) have one of the meanings given for                R^(Z3) or R^(Z4) and R^(Z5) together with the nitrogen                to which they are attached form a 5- or 6-membered                N-bound saturated heterocycle, which, in addition to the                nitrogen atom may comprise a further heteroatom,                selected from O, S and N as ring member and which is                unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl                radicals;    -   Q is CH₂ or CH₂CH₂, where one or two of the hydrogen atoms in        CH₂ or CH₂CH₂ may be replaced by halogen, C₁-C₄-alkyl or        C₁-C₄-haloalkyl;    -   R¹ is selected from hydrogen, halogen, C₁-C₆-alkyl, which is        unsubstituted or carries one C₁-C₄-alkoxy radical,        C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkoxy,        C₃-C₈-cycloalkyl, a radical NR^(1a)R^(1b), a radical        CH₂NR^(1a)R^(1b), C-bound 3- to 10-membered, saturated        heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1        heteroatoms, selected from O and S, as ring members, aryl,        aryl-CH₂, aryloxy, hetaryl, hetaryloxy or hetaryl-CH₂, wherein        the aryl, heterocyclyl and hetaryl rings ring in the last seven        radicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5        identical or different radicals R^(1c);        -   R^(1a) is hydrogen, C₁-C₈-alkyl, C₁-C₈-haloalkyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl,            C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl, benzyl, phenyl or            5- or 6-membered hetaryl, wherein the phenyl and hetaryl            rings in the last three radicals itself are unsubstituted or            carry 1, 2, 3, 4 or 5 identical or different radicals            R^(1c);        -   R^(1b) is hydrogen or C₁-C₄-alkyl; or        -   NR^(1a)R^(1b) is a 5- to 10-membered mono- or bicyclic            N-bound saturated heterocycle, which, in addition to the            nitrogen atom may comprise a further heteroatom, selected            from O, S and N as ring member and which is unsubstituted or            carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals;        -   R^(1c) is selected from the group consisting of halogen, CN,            OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;    -   R² has one of the meanings given for R¹ provided that R² is        different from hydrogen, if X¹ is N or CH, further provided that        R¹ is different from hydrogen, if X² is N;    -   R³ and R⁴ are independently of each other, selected from        hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₃-C₆-cycloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,        phenyl, C₁-C₄-haloalkoxy, a radical (CH₂)_(n)NR′R″, where R′ and        R″ have one of the meanings given for R^(Z1) and R^(Z2) and        wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to 7-membered,        saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or 1        heteroatoms, selected from O and S, as ring members, where the        heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5        identical or different radicals R^(6c), where R^(6c) has one of        the meanings given for R^(1c);    -   R² and R³ can form together with the carbon atoms, to which they        are bound, a fused 5- to 6-membered ring, which is itself        unsubstituted or carries 1, 2, 3 or 4 identical or different        radicals R^(23a);        -   R^(23a) is selected from the group consisting of halogen,            CN, OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl,            C₁-C₄-alkoxy and C₁-C₄-haloalkoxy;    -   R⁵ is hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkoxy,        (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given        for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4,        -   or C-bound 3- to 7-membered, saturated heterocyclyl having 1            or 2 nitrogen atoms and 0 or 1 heteroatoms, selected from O            and S, as ring members, where the heterocyclyl itself is            unsubstituted or carries 1, 2, 3, 4 or 5 identical or            different radicals R^(5c), where R^(5c) has one of the            meanings given for R^(1c);    -   R⁶, R⁷, R⁸ are, independently of each other, selected from        hydrogen, halogen, CN, C₁-C₄-alkyl, C₁-C₄-haloalkyl,        C₁-C₄-alkoxy, C₁-C₄-haloalkyoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,        (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings given        for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or        C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2        nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as        ring members, where the heterocyclyl itself is unsubstituted or        carries 1, 2, 3, 4 or 5 identical or different radicals R^(6c),        where R^(6c) has one of the meanings given for R^(1c);    -   R^(a) is C₃-C₆-cycloalkyl, C₁-C₆-haloalkyl or C₁-C₆-alkyl, which        is unsubstituted or carries one radical selected from        C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and a radical NR^(a1)R^(a2),        -   where R^(a1) and R^(a2) are independently of each other            selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,            C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl,        -   a radical NR^(a3)R^(a4) or a radical N═C(R^(a5))R^(a6),            where        -   R^(a3) and R^(a5) are independently of each other selected            from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and            C₁-C₄-alkoxy-C₁-C₄-alkyl;        -   R^(a4) and R^(a6) are independently of each other selected            from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,            C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl,            C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to 7-membered,            saturated heterocyclyl, 3- to 7-membered, saturated            heterocyclylmethyl, where heterocyclyl in the last two            mentioned radicals has 1 or 2 nitrogen atoms and 0 or 1            heteroatoms, selected from O and S, as ring members,            -   aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the                heterocycicyl, aryl and hetaryl rings ring in the last                six radicals themselves are unsubstituted or carry 1, 2,                3, 4 or 5 identical or different radicals R^(ac) where                R^(ac) has one of the meanings given for R^(1c);    -   and the pharmaceutically acceptable salts and the N-oxides        thereof.

The compounds of the present invention are potentiators of metabotropicglutamate (mGlu) receptor function, in particular they are potentiatorsof mGlu2 receptors. That is, the compounds of the present invention donot appear to bind at the glutamate recognition site on the mGlureceptor, but in the presence of glutamate or a glutamate agonist, thecompounds of the present invention increase mGlu receptor response. Thepresent potentiators are expected to have their effect at mGlu receptorsby virtue of their ability to increase the response of such receptors toglutamate or glutamate agonists, enhancing the function of thereceptors. It is recognized that the compounds of the present inventionwould be expected to increase the effectiveness of glutamate andglutamate agonists of the mGlu2 receptor. Thus, the compounds of thepresent invention are expected to be useful in the treatment of variousneurological and psychiatric disorders associated with glutamatedysfunction described to be treated herein and others that can betreated by such positive modulators as are appreciated by those skilledin the art.

The present invention also relates to pharmaceutical compositionscomprising at least one compound of the formula I, an N-oxide thereofand/or a pharmaceutically acceptable salt thereof, optionally togetherwith at least one physiologically acceptable carrier or auxiliarysubstance.

The present invention also relates to a method for treating a medicaldisorder, selected from neurological and psychiatric disordersassociated with glutamate dysfunction, said method comprisingadministering an effective amount of at least one compound of theformula I, an N-oxide thereof and/or a pharmaceutically acceptable saltthereof to a subject in need thereof.

The present invention also relates to a method for potentiation ofmetabotropic glutamate receptor activity in a mammal which comprisesadministering an effective amount of at least one compound of theformula I, an N-oxide thereof and/or a pharmaceutically acceptable saltthereof.

The present invention also relates to the use of the compounds offormula I, an N-oxide thereof and/or a pharmaceutically acceptable saltthereof, in therapy of a disease mentioned herein.

The compounds of the formula I, their N-oxides and theirpharmaceutically acceptable salts are particularly useful for preparing

-   -   a medicament for treating, controlling, ameliorating or reducing        the risk of anxiety in a mammalian;    -   a medicament for preparing a medicament for treating,        controlling, ameliorating or reducing the risk of depression in        a mammalian; a medicament for treating, controlling,        ameliorating or reducing the risk of migraine in a mammalian;    -   a medicament for treating, controlling, ameliorating or reducing        the risk of schizophrenia in a mammalian;    -   a medicament for treating, controlling, ameliorating or reducing        the risk of epilepsy in a mammalian;    -   a medicament for treating or ameliorating the symptoms        associated with substance-related disorders in a mammalian.

The present invention also relates to

-   -   a method for treating, controlling, ameliorating or reducing the        risk of anxiety in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of depression in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of schizophrenia in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of epilepsy in a mammalian;    -   a method for treating, controlling, ameliorating or reducing the        risk of migraine in a mammalian;    -   a method for treating or ameliorating the symptoms associated        with substance-related disorders in a mammalian;

which methods comprising administering an effective amount of at leastone compound of the formula I, an N-oxide thereof and/or apharmaceutically acceptable salt thereof to a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. The independentsyntheses of these diastereomers or their chromatographic separationsmay be achieved as known in the art by appropriate modification of themethodology disclosed herein. Their absolute stereochemistry may bedetermined by the x-ray crystallography of crystalline products orcrystalline intermediates which are derivatized, if necessary, with areagent containing an asymmetric center of known absolute configuration.

If desired, racemic mixtures of the compounds may be separated, so thatthe individual enantiomers are isolated. The separation can be carriedout by methods well known in the art, such as the conversion of theenantiomeric mixture of compounds I into a diastereomeric mixture, e.g.by reaction with a chiral auxiliary, such as a chiral acid or base,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Theenantiomeric mixture of the compounds can also be separated directly bychromatographic methods utilizing chiral stationary phases, whichmethods are well known in the art. Alternatively, any enantiomer of acompound may be obtained by stereoselective synthesis using opticallypure starting materials or reagents of known configuration by methodswell known in the art.

The term “pharmaceutically acceptable salts” refers to cationic oranionic salts compounds, wherein the counter ion is derived frompharmaceutically acceptable non-toxic bases or acids including inorganicor organic bases and inorganic or organic acids.

When the compound of formula I is acidic, salts may be prepared frompharmaceutically acceptable non-toxic bases, including inorganic andorganic bases. Salts derived from inorganic bases include salts, whereinthe counter ion is aluminium, ammonium, calcium, copper, ferric,ferrous, lithium, magnesium, manganic, manganous, potassium, sodium,zinc ion and the like. Particularly preferred are the ammonium, calcium,magnesium, potassium, and sodium ions. Salts derived frompharmaceutically acceptable organic non-toxic bases include salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, and basic ionexchange resins, such as arginine, betaine, caffeine, choline,dibenzylethylene-diamine, diethylamine, 2-diethylamino-ethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, trifluoroaceticacid, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonicacid, and the like. Particularly preferred are citric, hydrobromic,hydrochloric, maleic, phosphoric, sulfuric, fumaric, and tartaric acids.It will be understood that, as used herein, references to the compoundsof formula I are meant to also include the pharmaceutically acceptablesalts.

The present invention moreover relates to compounds of formula I asdefined above, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, the compounds according to the invention contain more of therespective isotope than this naturally occurs and thus is anyway presentin the compounds I.

The compounds of the formula I and their salts in the solid form mayexist in more than one crystal structure (polymorphism), and may also bein the form of hydrates or other solvates. The present inventionincludes any polymorph of the compound I or its salt as well as anyhydrate or other solvate.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

The term “halogen” denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine, chlorine or bromine.

The term “alkyl” as used herein and in the alkyl moieties ofalkoxyalkyl, alkylamino, dialkylamino and alkylsulfonyl denotes in eachcase a straight-chain or branched alkyl group having usually from 1 to 8carbon atoms, frequently from 1 to 6 carbon atoms, preferably 1 to 4carbon atoms, in particular 1 to 2 carbon atoms. Examples of an alkylgroup are methyl, ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl,iso-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethyl-propyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,n-heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl,1-propylpentyl, n-octyl, 1-methyloctyl, 2-methylheptyl, 1-ethylhexyl,2-ethylhexyl, 1,2-dimethylhexyl, 1-propylpentyl and 2-propylpentyl.

The term “haloalkyl” as used herein and in the haloalkyl moieties ofhaloalkylsulfonyl, denotes in each case a straight-chain or branchedalkyl group having usually from 1 to 8 carbon atoms, frequently from 1to 6 carbon atoms, preferably 1 to 4 carbon atoms, in particular 1 to 2carbon atoms, wherein the hydrogen atoms of this group are partially ortotally replaced with halogen atoms. Preferred haloalkyl moieties areselected from C₁-C₄-haloalkyl, more preferably from C₁-C₂-haloalkyl, inparticular from C₁-C₂-fluoroalkyl, such as fluoromethyl, difluoromethyl,trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2,2-difluoroethyl,2,2,2-trifluoroethyl, pentafluoroethyl or C₁-C₄-fluoroalkyl, such asfluoromethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,pentafluoroethyl, 2-fluoro-1-methylethyl, 2,2-difluoro-1-methylethyl,2,2,2-trifluoro-1-methylethyl, 2,2,2-trifluoro-1-trifluormethylethyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl and the like.

The term “alkoxy” as used herein denotes in each case a straight-chainor branched alkyl group which is bound via an oxygen atom and hasusually from 1 to 8 carbon atoms, frequently from 1 to 6 carbon atoms,preferably 1 to 4 carbon atoms. Examples of an alkoxy group are methoxy,ethoxy, n-propoxy, iso-propoxy, n-butyloxy, 2-butyloxy, iso-butyloxy,tert-butyloxy, pentyloxy, 1-methylbutyloxy, 2-methylbutyloxy,3-methylbutyloxy, 2,2-dimethylpropyloxy, 1-ethylpropyloxy, hexyloxy,1,1-dimethylpropyloxy, 1,2-dimethylpropyloxy, 1-methylpentyloyx,2-methylpentyloxy, 3-methylpentyloxy, 4-methylpentyloxy,1,1-dimethylbutyloyx, 1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy,2,2-dimethylbutyloxy, 2,3-dimethyl-butyloyx, 3,3-dimethylbutyloxy,1-ethylbutyloxy, 2-ethylbutyloxy, 1,1,2-trimethylpropyloxy,1,2,2-trimethylpropyloxy, 1-ethyl-1-methylpropyloxy,1-ethyl-2-methylpropyloxy n-heptyloxy, 1-methylhexyloxy,2-methylhexyloxy, 3-methylhexyloxy, 4-methylhexyloxy, 5-methylhexyloxy,1-ethylpentyloxy, 2-ethylpentyloxy, 3-ethylpentyloxy, 1-propylpentyloxy,n-octyloxy, 1-methyloctyloxy, 2-methylheptyloxy, 1-ethylhexyloxy,2-ethylhexyloxy, 1,2-dimethylhexyloxy, 1-propylpentoxy and2-propylpentyloxy.

The term “haloalkoxy” as used herein denotes in each case astraight-chain or branched alkoxy group having from 1 to 8 carbon atoms,frequently from 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, inparticular 1 or 2 carbon atoms, wherein the hydrogen atoms of this groupare partially or totally replaced with halogen atoms, in particularfluorine atoms. Preferred haloalkoxy moieties include C₁-C₄-haloalkoxy,in particular C₁-C₂-fluoroalkoxy, such as fluoromethoxy,difluoromethoxy, trifluoromethoxy, 1-fluoroethoxy, 2-fluoroethoyx,2,2-difluoroethoyx, 2,2,2-trifluoroethoxy, 2-chloro-2-fluoroethoxy,2-chloro-2,2-difluoroethoxy, 2,2-dichloro-2-fluorethoxy,2,2,2-trichloroethoxy, pentafluoroethoxy and the like.

The term “C₁-C₄-alkoxy-C₁-C₄-alkyl” as used herein denotes in each casea straight-chain or branched alkyl group which is bound via an oxygenatom to another alkyl group. Both alkyl groups have usually from 1 to 4carbon atoms, frequently from 1 to 3 carbon atoms, preferably 1 to2-carbon atoms. Examples are methoxymethyl, methoxyethyl,methoxy-n-propyl, methoxy-n-butyl, ethoxymethyl, ethoxyethyl,ethoxy-n-propyl, ethoxy-n-butyl, n-propoxymethyl, n-propoxyethyl,n-propoxy-n-propyl, n-propoxy-n-butyl, n-butoxymethyl, n-butoxyethyl,n-butoxy-n-propyl, n-butoxy-n-butyl.

The term “cycloalkyl” as used herein denotes in each case a mono- orbicyclic cycloaliphatic radical having usually from 3 to 8 C atoms or 3to 6 C atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, bicyclo[2.1.1]hexyl, bicyclo[3.1.1]heptyl,bicyclo[2.2.1]heptyl, and bicyclo[2.2.2]octyl.

The term “cycloalkylmethyl” as used herein denotes in each case a methylradical which is bound to a cycloalkyl group as defined above. Examplesare cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, especiallycyclopropylmethyl.

The term “aryl” as used herein denotes in each case a cyclic radicalselected from the group consisting of mono-, bi- or tricyclic aromaticradicals. Examples are phenyl, naphthyl and anthracyl, especiallyphenyl.

The term “aryl-CH₂” as used herein denotes in each case a methylradical, which is bound to an aryl group as described above. Examplesare benzyl, naphthylmethyl and anthracylmethyl, especially benzyl.

The term “aryloxy” as used herein denotes in each case an aryl groupwhich is bound via an oxygen atom. Examples are phenoxy, naphthoxy andanthracyloxy, especially phenoxy.

The term “hetaryl” as used herein denotes in each case a heterocyclicradical selected from the group consisting of monocyclic 5- or6-membered heteroaromatic radicals comprising as ring members 1, 2 or 3heteroatoms selected from N, O and S. Examples of 5- or 6-memberedheteroaromatic radicals include pyridyl, i.e. 2-, 3-, or 4-pyridyl,pyrimidinyl, i.e. 2-, 4- or 5-pyrimidinyl, pyrazinyl, pyridazinyl, i.e.3- or 4-pyridazinyl, thienyl, i.e. 2- or 3-thienyl, furyl, i.e. 2- or3-furyl, pyrrolyl, i.e. 2- or 3-pyrrolyl, oxazolyl, i.e. 2-, 3- or5-oxazolyl, isoxazolyl, i.e. 3-, 4- or 5-isoxazolyl, thiazolyl, i.e. 2-,3- or 5-thiazolyl, isothiazolyl, i.e. 3-, 4- or 5-isothiazolyl,pyrazolyl, i.e. 1-, 3-, 4- or 5-pyrazolyl, i.e. 1-, 2-, 4- or5-imidazolyl, oxadiazolyl, e.g. 2- or 5-[1,3,4]oxadiazolyl, 4- or5-(1,2,3-oxadiazol)yl, 3- or 5-(1,2,4-oxadiazol)yl, 2- or5-(1,3,4-oxadiazol)yl, thiadiazolyl, e.g. 2- or 5-(1,3,4-thiadiazol)yl,4- or 5-(1,2,3-thiadiazol)yl, 3- or 5-(1,2,4-thiadiazol)yl, triazolyl,e.g. 1H-, 2H- or 3H-1,2,3-triazol-4-yl, 2H-triazol-3-yl, 1H-, 2H-, or4H-1,2,4-triazolyl and tetrazolyl, i.e. 1H- or 2H-tetrazolyl.

The term “hetaryl-CH₂” as used herein denotes in each case a methylradical, which is bound to a hetaryl group as described above. Examplesare methylpyridyl, i.e. 2-, 3-, or 4-methylpyridyl, methylpyrimidinyl,i.e. 2-, 4- or 5-methylpyrimidinyl, methylpyrazinyl, methylpyridazinyl,i.e. 3- or 4-methylpyridazinyl, methylthienyl, i.e. 2- or3-methylthienyl, methylfuryl, i.e. 2- or 3-methylfuryl, methylpyrrolyl,i.e. 2- or 3-methylpyrrolyl, methyloxazolyl, i.e. 2-, 3- or5-methyloxazolyl, methylisoxazolyl, i.e. 3-, 4- or 5-methylisoxazolyl,methylthiazolyl, i.e. 2-, 3- or 5-methylthiazolyl, methylisothiazolyl,i.e. 3-, 4- or 5-methylisothiazolyl, methylpyrazolyl, i.e. 1-, 3-, 4- or5-methylpyrazolyl, i.e. 1-, 2-, 4- or 5-methylimidazolyl,methyloxadiazolyl, methylthiadiazolyl, methyltriazolyl andmethyltetrazolyl, i.e. 1H- or 2H-tetrazolyl.

N-bound heterocycles comprise saturated, non-aromatic heterocyclicrings, which are bound via the nitrogen-ring atom. It is 3- to10-membered and mono- or bicyclic, especially it is a 3- to 7-memberedmonocyclic ring. Examples therefore include aziridinyl, azetidinyl,azepanyl, azocanyl, azonanyl, azecanyl, pyrrolidinyl, piperidinyl,imidazolidinyl, pyrazolidinyl, piperazinyl, diazepanyl, diazocanyl,diazonanyl, diazecanyl, oxazolidinyl, isoxazolidinyl, morpholinyl,oxazinanyl, oxazepanyl, oxazocanyl, oxazonanyl, oxazecanyl,thiazolidinyl, isothiazolidinyl, thiazinanyl, thiomorpholinyl,thiazepanyl, thiazocanyl, thiazonanyl, thiazecanyl, oxadiazinanyl,oxadiazepanyl, oxadiazocanyl, oxadiazonanyl, oxadiazecanyl,thiodiazinanyl, thiadiazepanyl, thiadiazocanyl, thiadiazonanyl,thiadiazecanyl, decahydroquinolinyl, decahydroquinazolinyl,deachydronathyridinyl and the like.

The term “C-bound saturated heterocyclyl” as used herein denotes in eachcase a C-bound heterocyclic radical which is 3- to 10-membered,saturated and having 1 or 2 nitrogen atoms and 0 or 1 heteroatoms,selected from O and S, as ring members. Especially it is 3- to7-membered, monocyclic radical having 1 or 2 nitrogen atoms and 0 or 1heteroatoms, selected from O and S, as ring members. The heterocyclylitself can be unsubstituted or substituted. Examples therefore includeaziridinyl, azetidinyl, azepanyl, azocanyl, azonanyl, azecanyl,pyrrolidinyl, piperidinyl, imidazolidinyl, pyrazolidinyl, piperazinyl,diazepanyl, diazocanyl, diazonanyl, diazecanyl, oxazolidinyl,isoxazolidinyl, morpholinyl, oxazinanyl, oxazepanyl, oxazocanyl,oxazonanyl, oxazecanyl, thiazolidinyl, isothiazolidinyl, thiazinanyl,thiomorpholinyl, thiazepanyl, thiazocanyl, thiazonanyl, thiazecanyl,oxadiazinanyl, oxadiazepanyl, oxadiazocanyl, oxadiazonanyl,oxadiazecanyl, thiodiazinanyl, thiadiazepanyl, thiadiazocanyl,thiadiazonanyl, thiadiazecanyl, decahydroquinolinyl,decahydroquinazolinyl, deachydronathyridinyl and the like.

The term “C₁-C₄-hydrazide” as used herein denotes in each case ahydrazinyl group which is bound to a C₁-C₄-acyl group. Examples areformic acid hydrozide, acetic acid hydrozide, propionic acid hydrazideand butanoic acid hydrazide.

The term “covalent bond” as used in the definition of Z has to beunderstood as a covalent single bond.

Preferred compounds of the invention are those, wherein the variablesR^(a), Q, Z, X¹, X², X³ and X⁴ in formula I independently of each otherpreferably in any combination have one of the following meanings.

In a particular embodiment of the invention X¹ is C—R¹. In thisembodiment the radical R¹ is defined as above. In particular R¹ isselected from the group consisting of hydrogen, halogen, in particularchlorine or bromine, C₁-C₆-alkyl, in particular branched C₃-C₆-alkyl,such as isopropyl, isobutyl or tert.-butyl, C₁-C₆-haloalkyl, inparticular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂, CH₂CF₃ or CF₂CF₃,C₁-C₆-alkoxy, in particular C₁-C₃-alkoxy such as methoxy, ethoxy,n-propoxy, isopropoxy, C₁-C₄-haloalkoxy, in particularC₁-C₂-fluoroalkoxy such as OCF₃ or OCHF₂, C₃-C₈-cycloalkyl, inparticular C₃-C₆-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentylor cyclohexyl, a radical NR^(1a)R^(1b), wherein R^(1a) and R^(1b) are asdefined above and wherein at least one of R^(1a) and R^(1b) inparticular both R^(1a) and R^(1b), are different from hydrogen, aryl, inparticular phenyl, aryl-CH₂, in particular benzyl, aryloxy, inparticular phenoxy, and hetaryl, in particular pyridinyl, pyrimidinyl,thienyl or furyl, wherein the aryl, in particular phenyl, and hetarylrings in the last 4 mentioned radicals itself is unsubstituted orcarries 1, 2, 3, 4 or 5 identical or different radicals R^(1c).

In this particular embodiment, preference is given to compound, whereinR¹ is selected from the group consisting of phenyl, benzyl and phenoxy,wherein the phenyl ring in the last three radicals itself isunsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicalsR^(1c).

Likewise preference is given to compounds, wherein R¹ is selected fromthe group consisting of branched C₃-C₆-alkyl, C₃-C₆-cycloalkyl andC₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂,CH₂CF₃ or CF₂CF₃.

Particular examples of R¹ include CF₃, chlorine, amino, benzylamino,phenylamino, 4-methylpiperazin-1-yl, 4-morpholinyl, 1-piperazinyl,1-piperidinyl, 4-methylmorpholinyl, 4-methylpiperidin-1-yl,1-methylpiperidinyl, phenoxy, phenyl, 4-cyanophenyl,4-trifluoromethylphenyl, cyclobutyl, cyclopropyl, cyclopentyl,cyclohexyl and 4-fluorophenyl.

In a further particular embodiment of the invention, R¹ is a radicalNR^(1a)R^(1b) or C-bound 3- to 10-membered, in particular 3- to7-membered saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or1 heteroatom, selected from O and S, as ring members, where theheterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c). In this further particularembodiment, R¹ is especially a radical NR^(1a)R^(1b), where R^(1a) isselected from 2-methoxyethyl, 3-methoxy-n-propyl or 2-ethoxyethyl whileR^(1b) is methyl or ethyl or the radical NR^(1a)R^(1b) is morpholinyl,1,4-oxazepan-4-yl, 4-methylpiperazinyl, 1-pyrrolidinyl or 1-piperidinylor R¹ is 4-methylpiperidin-1-yl or 3-methylpyrrolidin-1-yl.

Particular examples of R¹ include CF₃, chloro, fluoro, amino,tert.-butyl, benzylamino, phenylamino, phenoxy, phenyl, 4-cyanophenyl,4-trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, 1,4-oxazepan-4-yl,4-methylpiperazinyl, 1-pyrrolidinyl, 1-piperidinyl,4-methylpiperidin-1-yl, 3-methylpyrrolidin-1-yl,N-(2-methoxyethyl)-N-methylamino, N-(3-methoxy-n-propyl)-N-methylamino,N-(2-ethoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,N-(3-methoxy-n-propyl)-N-ethylamino and N-(2-ethoxyethyl)-N-ethylamino.

In the radical NR^(1a)R^(1b), wherein at least one of R^(1a) and R^(1b),in particular both R^(1a) and R^(1b), are different from hydrogen, thevariable R^(1a) is particularly selected from the group consisting ofhydrogen, C₃-C₈-cycloalkyl, benzyl, phenyl or 5- or 6-membered hetaryl,wherein the phenyl and hetaryl rings in the last three radicals itselfare unsubstituted or carries 1, 2, 3, 4 or 5 identical or differentradicals R^(1c).

In the radical NR^(1a)R^(1b) the variable R^(1b) is preferably hydrogenor C₁-C₄-alkyl.

Where present, NR^(1a)R^(1b) may also preferably be a 5- to 10-membered,in particular 5- or 6-membered, mono- or bicyclic N-bound saturatedheterocycle, which, in addition to the nitrogen atom, may comprise afurther heteroatom selected from O, S and N as ring member and which isunsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals, examplesincluding 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl,1-pyrrolidinyl, N-methylpiperazin-1-yl, 1,4-oxazepan-4-yl,4-methylpiperidin-1-yl, or 3-methylpyrrolidin-1-yl.

In a further particular embodiment, R¹ is especially a radicalNR^(1a)R^(1b) where R^(1a) is selected from 2-methoxyethyl,3-methoxy-n-propyl or 2-ethoxyethyl while R^(1b) is methyl or ethyl.Examples are N-(2-methoxyethyl)-N-methylamino,N-(3-methoxy-n-propyl)-N-methylamino, N-(2-ethoxyethyl)-N-methylamino,N-(2-methoxyethyl)-N-ethylamino, N-(3-methoxy-n-propyl)-N-ethylamino,N-(2-ethoxyethyl)-N-ethylamino.

Where present, R^(1c) is selected from the group consisting of halogen,CN, OH, C₁-C₄-alkyl, such as methyl, ethyl, n-propyl or isopropyl,C₃-C₆-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, C₁-C₄-haloalkyl, in particular CHF₂, CF₃, CH₂CF₃ or CF₂CF₃,C₁-C₄-alkoxy, in particular methoxy or ethoxy, and C₁-C₄-haloalkoxy.

In a particular embodiment of the invention, X² is C—R². In thisembodiment, the radical R² is defined as above. In particular, R² isselected from the group consisting of hydrogen, halogen, in particularchlorine, C₁-C₆-alkyl, in particular branched C₃-C₆-alkyl, such asisopropyl, isobutyl or tert.-butyl, C₁-C₆-haloalkyl, in particularC₁-C₂-fluoroalkyl, such as CF₃, CHF₂, CH₂CF₃ or CF₂CF₃, C₁-C₆-alkoxy, inparticular C₁-C₃-alkoxy, such as methoxy, ethoxy, n-propoxy, isopropoxy,C₁-C₄-haloalkoxy, in particular C₁-C₂-fluoroalkoxy, such as OCF₃ orOCHF₂, C₃-C₈-cycloalkyl, in particular C₃-C₆-cycloalkyl, such ascyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, a radical(CH₂)_(n)NR^(2a)R^(2b), wherein n is 0 or 1 and R^(ea) has one of themeanings given for R^(1a) and R^(2b) has one of the meanings given forR^(1b), aryl, in particular phenyl, aryl-CH₂, in particular benzyl,aryloxy, in particular phenoxy, hetaryl, in particular pyridinyl,pyrimidinyl, thienyl or furyl, wherein the aryl, in particular phenyl,and hetaryl rings in the last 4 mentioned radicals itself isunsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicalsR^(2c), where R^(2c) has one of the meanings given for R^(1c).

In a particular embodiment of the invention, R² is selected from thegroup consisting of aryl, in particular from phenyl, arylmethyl, inparticular from benzyl and aryloxy, in particular from phenoxy, whereinthe aryl ring in the aforementioned radicals itself is unsubstituted orcarries 1, 2, 3, 4 or 5 identical or different radicals R.

In another particular embodiment of the invention, R² is selected fromthe group consisting of branched C₃-C₆-alkyl, C₃-C₆-cycloalkyl andC₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂,CH₂CF₃ or CF₂CF₃.

Particular examples of R² include CF₃, chlorine, amino, benzylamino,phenylamino, 4-methylpiperazin-1-yl, 4-morpholinyl, 1-piperidinyl,4-methylmorpholinyl, 1-methylpiperidinyl, phenoxy, phenyl,4-cyanophenyl, 4-trifluoromethylphenyl, cyclobutyl, cyclopropyl,cyclopentyl, cyclohexyl, 4-fluorophenyl.

In a further particular embodiment of the invention, R² is a radicalNR^(2a)R^(2b) or C-bound 3- to 10-membered, in particular 3- to7-membered saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or1 heteroatom, selected from O and S, as ring members, where theheterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(2c). In this further particularembodiment, R² is especially a radical NR^(2a)R^(2b) where R^(2a) isselected from 2-methoxyethyl, 3-methoxy-n-propyl or 2-ethoxyethyl whileR^(1b) is methyl or ethyl or the radical NR^(2a)R^(2b) is morpholinyl,1,4-oxazepan-4-yl, 4-methylpiperazinyl, 1-pyrrolidinyl or 1-piperidinylor R² is 4-methylpiperidin-1-yl or 3-methylpyrrolidin-1-yl.

Particular examples of R² include CF₃, chloro, fluoro, amino,tert.-butyl, benzylamino, phenylamino, phenoxy, phenyl, 4-cyanophenyl or4-trifluoromethylphenyl, 4-chlorophenyl, 4-fluorophenyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, morpholinyl, 1,4-oxazepan-4-yl,4-methylpiperazinyl, 1-pyrrolidinyl or 1-piperidinyl,4-methylpiperidin-1-yl, 3-methylpyrrolidin-1-yl,N-(2-methoxyethyl)-N-methylamino, N-(3-methoxy-n-propyl)-N-methylamino,N-(2-ethoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,N-(3-methoxy-n-propyl)-N-ethylamino or N-(2-ethoxyethyl)-N-ethylamino.

In the radical NR^(2a)R^(2b), wherein at least one of R^(2a) and R^(2b),in particular both R^(2a) and R^(2b), are different from hydrogen, thevariable R^(2a) is particularly selected from the group consisting ofhydrogen, C₃-C₈-cycloalkyl, benzyl, phenyl or 5- or 6-membered hetaryl,wherein the phenyl and hetaryl rings in the last three radicals itselfare unsubstituted or carries 1, 2, 3, 4 or 5 identical or differentradicals R^(2c).

In the radical NR^(2a)R^(2b) the variable R^(2b) is preferably hydrogenor C₁-C₄-alkyl.

Where present, NR^(2a)R^(2b) may also preferably be a 5- to 10-membered,in particular 5- or 6-membered, mono- or bicyclic N-bound saturatedheterocycle, which, in addition to the nitrogen atom, may comprise afurther heteroatom selected from O, S and N as ring member and which isunsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals, examplesincluding 4-morpholinyl, 4-thiomorpholinyl, 1-piperidinyl,1-pyrrolidinyl, N-methylpiperazin-1-yl, 1,4-oxazepan-4-yl,4-methylpiperidin-1-yl or 3-methylpyrrolidin-1-yl. In a furtherparticular embodiment, R² is especially a radical NR^(2a)R^(2b), whereR^(2a) is selected from 2-methoxyethyl, 3-methoxy-n-propyl or2-ethoxyethyl while R^(2b) is methyl or ethyl. Examples areN-(2-methoxyethyl)-N-methylamino, N-(3-methoxy-n-propyl)-N-methylamino,N-(2-ethoxyethyl)-N-methylamino, N-(2-methoxyethyl)-N-ethylamino,N-(3-methoxy-n-propyl)-N-ethylamino, N-(2-ethoxyethyl)-N-ethylamino.

Where present, R^(2c) is selected from the group consisting of halogen,CN, OH, C₁-C₄-alkyl, such as methyl, ethyl, n-propyl or isopropyl,C₃-C₆-cycloalkyl, in particular cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl, C₁-C₄-haloalkyl, in particular CHF₂, CF₃, CH₂CF₃ or CF₂CF₃,C₁-C₄-alkoxy, in particular methoxy or ethoxy, and C₁-C₄-haloalkoxy.

In a further particular embodiment of the invention, R² and R³ cantogether with the carbon atoms to which they are bound, form a fused 5-or 6-membered ring, which itself is unsubstituted or carries 1, 2, 3 or4 identical or different radicals R^(23a). More preferably, R² and R³can together with the carbon atoms to which they are bound, form a fusedbenzene ring which may be unsubstituted or carry 1 or 2 identical ordifferent radicals R^(23a).

In a particular embodiment, X¹ is CH, i.e. R¹ is hydrogen, and X² isC—R², where R² is as defined above. In particular, R² is selected fromaryl, CH₂-aryl, aryloxy, wherein the aryl ring in the last threeradicals itself is unsubstituted or carries 1, 2, 3, 4 or 5 identical ordifferent radicals R^(1c), branched C₃-C₆-alkyl, C₁-C₆-haloalkyl orC₃-C₆-cycloalkyl. In this embodiment R² is different from hydrogen.Especially, R² is selected from a group consisting of phenyl, benzyl,phenoxy, wherein the phenyl ring in the last three radicals itself isunsubstituted or carries 1, 2, 3, 4 or 5 identical or different radicalsR^(1c).

In a further embodiment, X¹ is N while X² is C—R², wherein R² is aryl,CH₂-aryl, aryloxy, branched C₃-C₆-alkyl, C₁-C₆-haloalkyl orC₃-C₆-cycloalkyl. In this particular embodiment, R² is in particularselected from a group consisting of phenyl, benzyl, phenoxy.

In a particular embodiment, X² is CH or N while X¹ is CR¹, where R¹ isdifferent from hydrogen and else wise defined as above.

X³ is in particular C—R³, where R³ is as defined above and wherein R³ isin R^(3i) particular selected from the group consisting of hydrogen,halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy. Especially R³ is selected fromthe group consisting of hydrogen, chlorine, methyl and trifluoromethyl.

X⁴ is in particular C—R⁴, where R⁴ is as defined above and wherein R⁴ isin particular selected from the group consisting of hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. Especially R⁴ is selected from the groupconsisting of hydrogen, chlorine, methyl and trifluoromethyl.

The radical R^(a) is selected from the group consisting ofC₃-C₆-cycloalkyl, in particular C₃-C₄-cycloalkyl, such as cyclopropyl,C₁-C₆-haloalkyl, in particular C₁-C₂-fluoroalkyl, such as CF₃, CHF₂,CH₂CF₃, CF₂CF₃, C₁-C₆-alkyl, in particular C₂-C₆-alkyl, especiallyC₃-C₆-alkyl, such as n-propyl, n-butyl, iso-butyl, n-pentyl, theaforementioned alkyl radical can be unsubstituted or carries one radicalselected from the group consisting of C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,in particular methoxy, ethoxy or OCF₃. In particular, R^(a) is selectedfrom the group consisting of ethyl, n-propyl, n-butyl, cyclopropyl,2-methoxyethyl, 2-ethoxyethyl, 2,2,2-trifluoroethyl and2-trifluoromethoxyethyl. In a particular embodiment of the invention,R^(a) is C₂-C₆-alkyl, especially C₂-C₄-alkyl which carries one radicalselected from the group consisting of C₁-C₄-alkoxy and C₁-C₄-haloalkoxy,in particular methoxy, ethoxy or OCF₃, such as 2-methoxyethyl,2-ethoxyethyl, 2,2,2-trifluoroethyl and 2-trifluoromethoxyethyl. Inanother particular embodiment, R^(a) is a radical NR^(a3)R^(a4), whereR^(a3) has one of the aforementioned meanings and is in particularselected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(a4) hasone of the aforementioned meanings and is in particular selected fromhydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3- to7-membered, saturated heterocyclyl, 3- to 7-membered, saturatedheterocyclylmethyl, where heterocyclyl in the last two mentionedradicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms, selected fromO and S, as ring members, aryl, aryl-CH₂, hetaryl and hetaryl-CH₂,wherein the heterocyclyl, aryl and hetaryl rings in the last sixradicals themselves are unsubstituted or carry 1, 2, 3, 4 or 5 identicalor different radicals R^(ac), where R^(ac) has one of the meanings givenfor R^(1c).

Where present, R^(a1) and R^(a2) are independently of each other inparticular selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl. Especially, R^(a1)is selected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl andC₁-C₄-alkoxy-C₁-C₄-alkyl, while R^(a2) is selected from hydrogen andC₁-C₄-alkyl.

Where present, R^(a3) is selected from hydrogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl andC₁-C₄-alkoxy-C₁-C₄-alkyl.

Where present, R^(a4) is selected from hydrogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, C-bound 3 to 10 membered, saturatedheterocyclyl, 3- to 7-membered, saturated heterocyclylmethyl, whereheterocyclyl in the last two mentioned radicals has 1 or 2 nitrogenatoms and 0 or 1 heteroatoms, selected from O and S, as ring members,aryl, aryl-CH₂, hetaryl and hetaryl-CH₂, wherein the heterocyclyl, aryland hetaryl rings in the last six radicals themselves are unsubstitutedor carry 1, 2, 3, 4 or 5 identical or different radicals R^(ac), whereR^(ac) has one of the meanings given for R^(1c).

The radical Z is selected from the group consisting of a covalent bond,CR^(Za)R^(Zb), O, S or NR^(Zc), in particular a covalent bond, O and NH,especially O and NH.

If Z is a radical CR^(Za)R^(Zb), R^(Za) and R^(Zb) are in particularselected from the group consisting of hydrogen, halogen and C₁-C₄-alkyl.Especially R^(Za) and R^(Zb) are hydrogen.

If Z is a radical NR^(Zc), R^(Zc) is in particular selected from thegroup consisting of hydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, which is unsubstituted or carriesone radical selected from C₁-C₄-alkoxy and NR^(Z1)R^(Z2), S(O)₂R^(Z3) ora radical S(O)₂NR^(Z4)R^(Z5).

Where present, R^(Z1) and R^(Z2) are independently of each other inparticular selected from the group consisting of hydrogen,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl andC₁-C₄-alkoxy-C₁-C₄-alkyl. In particular, R^(Z1) and R^(Z2) may also formtogether with the nitrogen to which they are attached a 5- or 6-memberedN-bound saturated heterocycle, which, in addition to the nitrogen atom,may comprise a further heteroatom, selected from O, S and N as ringmember and which is unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkylradicals, examples including 4-morpholinyl, 4-thiomorpholinyl,1-piperidinyl, 1-pyrrolidinyl or N-methylpiperazin-1-yl.

Where present, R^(Z3) is in particular selected from C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl, phenyl or benzyl, wherein thephenyl ring in the last two mentioned itself is unsubstituted or carries1, 2, 3, 4 or 5 identical or different radicals selected from halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.Especially, R^(Z3), where present, is C₁-C₄-alkyl such as methyl.

Where present, R^(Z4) and R^(Z5) have in particular one of theparticular meanings given for R^(Z1) and R^(Z2).

In a particular embodiment Z is O or NH.

In another embodiment Z is a covalent bond.

Q is CH₂ or CH₂CH₂. In a particular embodiment Q is CH₂. In anotherparticular embodiment Q is CH₂CH₂.

A particular embodiment of the invention relates to compounds accordingto formula I, their salts and N-oxides, where X¹, X², X³ and X⁴ are CR¹,CR², CR³ and CR⁴, respectively, wherein R¹, R², R³ and R⁴ are as definedabove. According to the invention R² is different from hydrogen, if R¹is hydrogen, while R¹ is different from hydrogen, if R² is hydrogen. Inparticular, one of Wand R² is hydrogen. In this particular embodiment,R³ is in particular selected from the group consisting of hydrogen,halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the groupconsisting of hydrogen, chlorine, methyl and trifluoromethyl. In thisparticular embodiment, R⁴ is in particular selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, methyl andtrifluoromethyl. Especially one or both of the radicals R³ and R⁴ aredifferent from hydrogen with a particular preference given to compounds,wherein R³ is hydrogen and R⁴ is halogen, such as chlorine.

A further particular embodiment of the invention relates to compoundsaccording to formula I, their salts and N-oxides, where X¹ is N whileX², X³ and X⁴ are CR², CR³ and CR⁴, respectively, wherein R², R³ and R⁴are as defined above. In this particular embodiment, R² is differentfrom hydrogen. In this particular embodiment, R³ is in particularselected from the group consisting of hydrogen, halogen, C₁-C₄-alkyl andC₁-C₄-alkoxy, especially from the group consisting of hydrogen,chlorine, methyl and trifluoromethyl. In this particular embodiment, R⁴is in particular selected from the group consisting of hydrogen,halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from the groupconsisting of hydrogen, chlorine, methyl and trifluoromethyl. Especiallyone or both of the radicals R³ and R⁴ are different from hydrogen with aparticular preference given to compounds, wherein R³ is hydrogen and R⁴is halogen, such as chlorine.

Another particular embodiment of the invention relates to compoundsaccording to formula I, their salts and N-oxides, where X² is N whileX¹, X³ and X⁴ are CR¹, CR³ and CR⁴, respectively, wherein R¹, R³ and R⁴are as defined above. In this particular embodiment, R¹ is differentfrom hydrogen and R³ is in particular selected from the group consistingof hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy, especially from thegroup consisting of hydrogen, chlorine, methyl and trifluoromethyl. Inthis particular embodiment, R⁴ is in particular selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, methyl andtrifluoromethyl. Especially one or both of the radicals R³ and R⁴ aredifferent from hydrogen with a particular preference given to compounds,wherein R³ is hydrogen and R⁴ is halogen, such as chlorine.

Another particular embodiment of the invention relates to compoundsaccording to formula I, their salts and N-oxides, where X³ is N whileX¹, X² and X⁴ are CR¹, CR² and CR⁴, respectively, wherein R¹, R² and R⁴are as defined above. According to the invention R² is different fromhydrogen, if R¹ is hydrogen, while R¹ is different from hydrogen, if R²is hydrogen. In particular, one of R¹ and R² is hydrogen. In thisparticular embodiment, R⁴ is in particular selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, methyl andtrifluoromethyl.

Another particular embodiment of the invention relates to compoundsaccording to formula I, their salts and N-oxides, where X⁴ is N whileX¹, X² and X³ are CR¹, CR² and CR³, respectively, wherein R¹, R², and R³are as defined above. According to the invention, R² is different fromhydrogen, if R¹ is hydrogen, while R¹ is different from hydrogen, if R²is hydrogen. In particular, one of R¹ and R² is hydrogen. In thisparticular embodiment, R³ is in particular selected from the groupconsisting of hydrogen, halogen, C₁-C₄-alkyl and C₁-C₄-alkoxy,especially from the group consisting of hydrogen, chlorine, methyl andtrifluoromethyl.

Furthermore, one embodiment of the invention relates to compounds offormula I, their salts and N-oxides, wherein Z is bound to Y¹, i.e. Y¹is C, Y² is C—R⁶, Y³ is C—R⁷ and Y⁴ is C—R⁸ or one of Y², Y³ or Y⁴ mayalso be N. Where occurring, R⁶, R⁷ and R⁸ are independently of eachother selected from hydrogen, halogen, C₁-C₄-alkyl,

C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y² is C—R⁶, Y³ is C—R⁷ and Y⁴ isC—R⁸. In this particular embodiment, R⁶, R⁷ and R⁸ are especiallyhydrogen.

Another embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein Z is bound to Y², i.e. Y² is C, Y¹ isC—R⁵, Y³ is C—R⁷ and Y⁴ is C—R⁸ or one of Y¹, Y³ or Y⁴ may also be N.Where occurring, R⁵, R⁷ and R⁸ are independently of each otherpreferably selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y¹ is C—R⁵, Y³ is C—R⁷ and Y⁴ isC—R⁸. In this particular embodiment, R⁵ is in particular hydrogen,chlorine, methyl, or methoxy, especially hydrogen. In this particularembodiment, R⁷ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein Z is bound to Y³, i.e. Y³ is C, Y¹ isC—R⁵, Y² is C—R⁶ and Y⁴ is C—R⁸ or one of Y¹, Y³ or Y⁴ may also be N.Where occurring, R⁵, R⁷ and R⁸ are independently of each otherpreferably selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y¹ is C—R⁵, Y² is C—R⁶ and Y⁴ isC—R⁸. In this particular embodiment, R⁵ is in particular hydrogen,chlorine, methyl, or methoxy, especially hydrogen. In this particularembodiment, R⁶ and R⁸ are especially hydrogen.

Another embodiment of the invention relates to compounds of formula I,their salts and N-oxides, wherein Z is bound to Y⁴, i.e. Y⁴ is C, Y¹ isC—R⁵, Y² is C—R⁶ and Y³ is C—R⁷ or one of Y¹, Y² or Y³ may also be N.Where occurring, R⁵, R⁶ and R⁷ are independently of each otherpreferably selected from hydrogen, halogen, C₁-C₄-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, CN, (CH₂)_(n)NR′R″, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy, in particular from hydrogen, halogen,C₁-C₄-alkyl and C₁-C₄-alkoxy. In this particular embodiment, preferenceis given to those compounds, wherein Y¹ is CR⁵, Y² is CR⁶ and Y³ isC—R⁷. In this particular embodiment, R⁵ is in particular hydrogen,chlorine, methyl, or methoxy, especially hydrogen. In this particularembodiment, R⁶ and R⁷ are especially hydrogen.

The compounds of the general formulae Ia, Ib and Ic, wherein Z, Q, X¹,R², R³, R⁴, R⁵ and R^(a) are as defined above and their pharmaceuticallyacceptable salts, represent per se preferred embodiments of the presentinvention.

A particular embodiment of the invention relates to compounds offormulae Ia, Ib, and Ic, wherein X¹ is CH and Z, Q, R², R³, R⁴, R⁵ andR^(a) are as defined above, but R² is not hydrogen. In particular Q isCH₂ or CH₂CH₂. Preferably R⁵ is hydrogen. In particular Z is O, NH, CH₂or a covalent bond, especially O or NH.

A further embodiment of the invention relates to compounds of formulaeIa, Ib and Ic, wherein X¹ is N and Z, Q, R², R³, R⁴, R⁵ and R^(a) are asdefined above, but R² is not hydrogen. In particular Q is CH₂ or CH₂CH₂.Preferably R⁵ is hydrogen. In particular Z is O, NH, CH₂ or a covalentbond, especially O or NH.

More preferably are compounds of the general formulae Ia, Ib and Icwhich are indicated in the Tables 1 to 296 below. The meanings for X¹,R²; R³ and R⁴ indicated in the Tables A, B and C below representembodiments of the invention which are likewise preferred independentlyof one another and especially in combination.

Table 1

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 2

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 3

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 4

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 5

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 6

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 7

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 8

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 9

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is C₂H₅, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 10

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 11

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 12

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 13

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 14

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 15

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 16

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 17

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 18

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₃H₇, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 19

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 20

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 21

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 22

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 23

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 24

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 25

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 26

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 27

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is n-C₄H₉, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 28

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 29

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 30

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 31

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 32

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 33

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 34

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 35

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 36

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂,R^(a) is 2-methoxyethyl, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 37

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 38

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 39

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 40

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 41

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 42

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 43

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 44

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 45

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is C₂H₅, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 46

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 47

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 48

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 49

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 50

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 51

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 52

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 53

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 54

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₃H₇, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 55

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 56

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 57

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 58

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 59

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 60

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 61

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 62

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 63

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is n-C₄H₉, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ and thecombination of R¹, R² and R⁴ for a compound in each case corresponds toone row of Table A.

Table 64

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is hydrogen, R⁵ is hydrogen and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 65

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is methyl, R⁵ is hydrogen and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 66

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is hydrogen, R⁵ is methyl and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 67

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is methyl, R⁵ is methyl and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 68

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is chlorine, R⁵ is hydrogen and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 69

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is hydrogen, R⁵ is chlorine and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 70

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is chlorine, R⁵ is chlorine and X¹ is C—R¹and the combination of R¹, R² and R⁴ for a compound in each casecorresponds to one row of Table A.

Table 71

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is methyl, R⁵ is chlorine and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Table 72

Compounds of the formulae Ia, Ib and Ic, in which Z is O, Q is CH₂CH₂,R^(a) is 2-methoxyethyl, R³ is chlorine, R⁵ is methyl and X¹ is C—R¹ andthe combination of R¹, R² and R⁴ for a compound in each case correspondsto one row of Table A.

Tables 73 to 144

Compounds of the formulae Ia, Ib and Ic, in which Z is NH, Q, R^(a), R³,R⁵ and X¹ correspond to those given in tables 1 to 72 and R¹, R² and R⁴are as defined in one row of Table A.

Tables 145 to 216

Compounds of the formulae Ia, Ib and Ic, in which Z is CH₂, Q, R^(a),R³, R⁵ and X¹ correspond to those given in tables 1 to 72 and R¹, R² andR⁴ are as defined in one row of Table A.

Tables 217 to 288

Compounds of the formulae Ia, Ib and Ic, in which Z is a covalent bond,Q, R^(a), R³, R⁵ and X¹ correspond to those given in tables 1 to 72 andR¹, R² and R⁴ are as defined in one row of Table A.

TABLE A No. R¹ R² R⁴ A1 H H H A2 CH₃ H H A3 C₂H₅ H H A4 n-C₃H₇ H H A5CF₃ H H A6 CHF₂ H H A7 CH₂CF₃ H H A8 OCH₃ H H A9 OCH₂—CH₃ H H A10 OCF₃ HH A11 OCH₂—CF₃ H H A12 Phenyl H H A13 Phenoxy H H A14 Benzyl H H A15 ClH H A16 Br H H A17 I H H A18 NH₂ H H A19 NH-Phenyl H H A20 CN H H A21NH-Benzyl H H A22 4-cyanophenyl H H A23 4-Morpholinyl H H A244-Methylpiperazin-1-yl H H A25 Piperazin-1-yl H H A26 [1,4]Oxazepan-4-ylH H A27 H CH₃ H A28 CH₃ CH₃ H A29 C₂H₅ CH₃ H A30 n-C₃H₇ CH₃ H A31 CF₃CH₃ H A32 CHF₂ CH₃ H A33 CH₂CF₃ CH₃ H A34 OCH₃ CH₃ H A35 OCH₂—CH₃ CH₃ HA36 OCF₃ CH₃ H A37 OCH₂—CF₃ CH₃ H A38 Phenyl CH₃ H A39 Phenoxy CH₃ H A40Benzyl CH₃ H A41 Cl CH₃ H A42 Br CH₃ H A43 I CH₃ H A44 NH₂ CH₃ H A45NH-Phenyl CH₃ H A46 CN CH₃ H A47 NH-Benzyl CH₃ H A48 4-cyanophenyl CH₃ HA49 4-Morpholinyl CH₃ H A50 4-Methylpiperazin-1-yl CH₃ H A51Piperazin-1-yl CH₃ H A52 [1,4]Oxazepan-4-yl CH₃ H A53 H C₂H₅ H A54 Hn-C₃H₇ H A55 H CF₃ H A56 H CHF₂ H A57 H CH₂CF₃ H A58 H OCH₃ H A59 HOCH₂—CH₃ H A60 H OCF₃ H A61 H OCH₂—CF₃ H A62 H Phenyl H A63 H Phenoxy HA64 H Benzyl H A65 H Cl H A66 H Br H A67 H I H A68 H NH₂ H A69 HNH-Phenyl H A70 H CN H A71 H NH-Benzyl H A72 H 4-cyanophenyl H A73 H4-Morpholinyl H A74 H 4-Methylpiperazin-1-yl H A75 H Piperazin-1-yl HA76 H [1,4]Oxazepan-4-yl H A77 CH₃ CH₃ H A78 CH₃ C₂H₅ H A79 CH₃ n-C₃H₇ HA80 CH₃ CF₃ H A81 CH₃ CHF₂ H A82 CH₃ CH₂CF₃ H A83 CH₃ OCH₃ H A84 CH₃OCH₂—CH₃ H A85 CH₃ OCF₃ H A86 CH₃ OCH₂—CF₃ H A87 CH₃ Phenyl H A88 CH₃Phenoxy H A89 CH₃ Benzyl H A90 CH₃ Cl H A91 CH₃ Br H A92 CH₃ I H A93 CH₃NH₂ H A94 CH₃ NH-Phenyl H A95 CH₃ CN H A96 CH₃ NH-Benzyl H A97 CH₃4-cyanophenyl H A98 CH₃ 4-Morpholinyl H A99 CH₃ 4-Methylpiperazin-1-yl HA100 CH₃ Piperazin-1-yl H A101 CH₃ [1,4]Oxazepan-1-yl H A102 H H CH₃A103 CH₃ H CH₃ A104 C₂H₅ H CH₃ A105 n-C₃H₇ H CH₃ A106 CF₃ H CH₃ A107CHF₂ H CH₃ A108 CH₂CF₃ H CH₃ A109 OCH₃ H CH₃ A110 OCH₂—CH₃ H CH₃ A111OCF₃ H CH₃ A112 OCH₂—CF₃ H CH₃ A113 Phenyl H CH₃ A114 Phenoxy H CH₃ A115Benzyl H CH₃ A116 Cl H CH₃ A117 Br H CH₃ A118 I H CH₃ A119 NH₂ H CH₃A120 NH-Phenyl H CH₃ A121 CN H CH₃ A122 NH-Benzyl H CH₃ A1234-cyanophenyl H CH₃ A124 4-Morpholinyl H CH₃ A125 4-Methylpiperazin-1-ylH CH₃ A126 Piperazin-1-yl H CH₃ A127 [1,4]Oxazepan-4-yl H CH₃ A128 H CH₃CH₃ A129 CH₃ CH₃ CH₃ A130 C₂H₅ CH₃ CH₃ A131 n-C₃H₇ CH₃ CH₃ A132 CF₃ CH₃CH₃ A133 CHF₂ CH₃ CH₃ A134 CH₂CF₃ CH₃ CH₃ A135 OCH₃ CH₃ CH₃ A136OCH₂—CH₃ CH₃ CH₃ A137 OCF₃ CH₃ CH₃ A138 OCH₂—CF₃ CH₃ CH₃ A139 Phenyl CH₃CH₃ A140 Phenoxy CH₃ CH₃ A141 Benzyl CH₃ CH₃ A142 Cl CH₃ CH₃ A143 Br CH₃CH₃ A144 I CH₃ CH₃ A145 NH₂ CH₃ CH₃ A146 NH-Phenyl CH₃ CH₃ A147 CN CH₃CH₃ A148 NH-Benzyl CH₃ CH₃ A149 4-cyanophenyl CH₃ CH₃ A150 4-MorpholinylCH₃ CH₃ A151 4-Methylpiperazin-1-yl CH₃ CH₃ A152 Piperazin-1-yl CH₃ CH₃A153 [1,4]Oxazepan-4-yl CH₃ CH₃ A154 H C₂H₅ CH₃ A155 H n-C₃H₇ CH₃ A156 HCF₃ CH₃ A157 H CHF₂ CH₃ A158 H CH₂CF₃ CH₃ A159 H OCH₃ CH₃ A160 HOCH₂—CH₃ CH₃ A161 H OCF₃ CH₃ A162 H OCH₂—CF₃ CH₃ A163 H Phenyl CH₃ A164H Phenoxy CH₃ A165 H Benzyl CH₃ A166 H Cl CH₃ A167 H Br CH₃ A168 H I CH₃A169 H NH₂ CH₃ A170 H NH-Phenyl CH₃ A171 H CN CH₃ A172 H NH-Benzyl CH₃A173 H 4-cyanophenyl CH₃ A174 H 4-Morpholinyl CH₃ A175 H4-Methylpiperazin-1-yl CH₃ A176 H Piperazin-1-yl CH₃ A177 H[1,4]Oxazepan-4-yl CH₃ A178 CH₃ CH₃ CH₃ A179 CH₃ C₂H₅ CH₃ A180 CH₃n-C₃H₇ CH₃ A181 CH₃ CF₃ CH₃ A182 CH₃ CHF₂ CH₃ A183 CH₃ CH₂CF₃ CH₃ A184CH₃ OCH₃ CH₃ A185 CH₃ OCH₂—CH₃ CH₃ A186 CH₃ OCF₃ CH₃ A187 CH₃ OCH₂—CF₃CH₃ A188 CH₃ Phenyl CH₃ A189 CH₃ Phenoxy CH₃ A190 CH₃ Benzyl CH₃ A191CH₃ Cl CH₃ A192 CH₃ Br CH₃ A193 CH₃ I CH₃ A194 CH₃ NH₂ CH₃ A195 CH₃NH-Phenyl CH₃ A196 CH₃ CN CH₃ A197 CH₃ NH-Benzyl CH₃ A198 CH₃4-cyanophenyl CH₃ A199 CH₃ 4-Morpholinyl CH₃ A200 CH₃4-Methylpiperazin-1-yl CH₃ A201 CH₃ Piperazin-1-yl CH₃ A202 CH₃[1,4]Oxazepan-4-yl CH₃ A203 H H Cl A204 CH₃ H Cl A205 C₂H₅ H Cl A206n-C₃H₇ H Cl A207 CF₃ H Cl A208 CHF₂ H Cl A209 CH₂CF₃ H Cl A210 OCH₃ H ClA211 OCH₂—CH₃ H Cl A212 OCF₃ H Cl A213 OCH₂—CF₃ H Cl A214 Phenyl H ClA215 Phenoxy H Cl A216 Benzyl H Cl A217 Cl H Cl A218 Br H Cl A219 I H ClA220 NH₂ H Cl A221 NH-Phenyl H Cl A222 CN H Cl A223 NH-Benzyl H Cl A2244-cyanophenyl H Cl A225 4-Morpholinyl H Cl A226 4-Methylpiperazin-1-yl HCl A227 Piperazin-1-yl H Cl A228 [1,4]Oxazepan-4-yl H Cl A229 H CH₃ ClA230 CH₃ CH₃ Cl A231 C₂H₅ CH₃ Cl A232 n-C₃H₇ CH₃ Cl A233 CF₃ CH₃ Cl A234CHF₂ CH₃ Cl A235 CH₂CF₃ CH₃ Cl A236 OCH₃ CH₃ Cl A237 OCH₂—CH₃ CH₃ ClA238 OCF₃ CH₃ Cl A239 OCH₂—CF₃ CH₃ Cl A240 Phenyl CH₃ Cl A241 PhenoxyCH₃ Cl A242 Benzyl CH₃ Cl A243 Cl CH₃ Cl A244 Br CH₃ Cl A245 I CH₃ ClA246 NH₂ CH₃ Cl A247 NH-Phenyl CH₃ Cl A248 CN CH₃ Cl A249 NH-Benzyl CH₃Cl A250 4-cyanophenyl CH₃ Cl A251 4-Morpholinyl CH₃ Cl A2524-Methylpiperazin-1-yl CH₃ Cl A253 Piperazin-1-yl CH₃ Cl A254[1,4]Oxazepan-4-yl CH₃ Cl A255 H C₂H₅ Cl A256 H n-C₃H₇ Cl A257 H CF₃ ClA258 H CHF₂ Cl A259 H CH₂CF₃ Cl A260 H OCH₃ Cl A261 H OCH₂—CH₃ Cl A262 HOCF₃ Cl A263 H OCH₂—CF₃ Cl A264 H Phenyl Cl A265 H Phenoxy Cl A266 HBenzyl Cl A267 H Cl Cl A268 H Br Cl A269 H I Cl A270 H NH₂ Cl A271 HNH-Phenyl Cl A272 H CN Cl A273 H NH-Benzyl Cl A274 H 4-cyanophenyl ClA275 H 4-Morpholinyl Cl A276 H 4-Methylpiperazin-1-yl Cl A277 HPiperazin-1-yl Cl A278 H [1,4]Oxazepan-4-yl Cl A279 CH₃ CH₃ Cl A280 CH₃C₂H₅ Cl A281 CH₃ n-C₃H₇ Cl A282 CH₃ CF₃ Cl A283 CH₃ CHF₂ Cl A284 CH₃CH₂CF₃ Cl A285 CH₃ OCH₃ Cl A286 CH₃ OCH₂—CH₃ Cl A287 CH₃ OCF₃ Cl A288CH₃ OCH₂—CF₃ Cl A289 CH₃ Phenyl Cl A290 CH₃ Phenoxy Cl A291 CH₃ BenzylCl A292 CH₃ Cl Cl A293 CH₃ Br Cl A294 CH₃ I Cl A295 CH₃ NH₂ Cl A296 CH₃NH-Phenyl Cl A297 CH₃ CN Cl A298 CH₃ NH-Benzyl Cl A299 CH₃ 4-cyanophenylCl A300 CH₃ 4-Morpholinyl Cl A301 CH₃ 4-Methylpiperazin-1-yl Cl A302 CH₃Piperazin-1-yl Cl A303 CH₃ [1,4]Oxazepan-4-yl Cl

Table 289

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is O and Q is CH₂ and the combination of R², R⁴ and R^(a) for acompound in each case corresponds to one line of Table B.

Table 290

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is O and Q is CH₂CH₂ and the combination of R², R⁴ and R^(a) for acompound in each case corresponds to one line of Table B.

Table 291

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is NH and Q is CH₂ and the combination of R², R⁴ and R^(a) for acompound in each case corresponds to one line of Table B.

Table 292

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is NH and Q is CH₂CH₂ and the combination of R², R⁴ and R^(a) for acompound in each case corresponds to one line of Table B.

Table 293

Compounds of the formulae Ia, Ib and Ic in which R⁵ is hydrogen, X¹ isN, Z is CH₂ and Q is CH₂ and the combination of R², R⁴ and R^(a) for acompound in each case corresponds to one line of Table B.

Table 294

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is CH₂ and Q is CH₂CH₂ and the combination of R², R⁴ and R^(a) fora compound in each case corresponds to one line of Table B.

Table 295

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is a covalent bond and Q is CH₂ and the combination of R², R⁴ andR^(a) for a compound in each case corresponds to one line of Table B.

Table 296

Compounds of the formulae Ia, Ib and Ic, in which R⁵ is hydrogen, X¹ isN, Z is a covalent bond and Q is CH₂CH₂ and the combination of R², R⁴and R^(a) for a compound in each case corresponds to one line of TableB.

TABLE B No. R² R⁴ R^(a) B1 CH₃ H C₂H₅ B2 n-C₂H₅ H C₂H₅ B3 n-C₃H₇ H C₂H₅B4 CF₃ H C₂H₅ B5 CHF₂ H C₂H₅ B6 CH₂CF₃ H C₂H₅ B7 OCH₃ H C₂H₅ B8 OCH₂—CH₃H C₂H₅ B9 OCF₃ H C₂H₅ B10 OCH₂—CF₃ H C₂H₅ B11 Phenyl H C₂H₅ B12 PhenoxyH C₂H₅ B13 Benzyl H C₂H₅ B14 Cl H C₂H₅ B15 Br H C₂H₅ B16 I H C₂H₅ B17NH₂ H C₂H₅ B18 NH-Phenyl H C₂H₅ B19 CN H C₂H₅ B20 NH-Benzyl H C₂H₅ B214-cyanophenyl H C₂H₅ B22 4-Morpholinyl H C₂H₅ B23 4-Methylpiperazin-1-ylH C₂H₅ B24 Piperazin-1-yl H C₂H₅ B25 CH₃ CH₃ C₂H₅ B26 n-C₂H₅ CH₃ C₂H₅B27 n-C₃H₇ CH₃ C₂H₅ B28 CF₃ CH₃ C₂H₅ B29 CHF₂ CH₃ C₂H₅ B30 CH₂CF₃ CH₃C₂H₅ B31 OCH₃ CH₃ C₂H₅ B32 OCH₂—CH₃ CH₃ C₂H₅ B33 OCF₃ CH₃ C₂H₅ B34OCH₂—CF₃ CH₃ C₂H₅ B35 Phenyl CH₃ C₂H₅ B36 Phenoxy CH₃ C₂H₅ B37 BenzylCH₃ C₂H₅ B38 Cl CH₃ C₂H₅ B39 Br CH₃ C₂H₅ B40 I CH₃ C₂H₅ B41 NH₂ CH₃ C₂H₅B42 NH-Phenyl CH₃ C₂H₅ B43 CN CH₃ C₂H₅ B44 NH-Benzyl CH₃ C₂H₅ B454-cyanophenyl CH₃ C₂H₅ B46 4-Morpholinyl CH₃ C₂H₅ B474-Methylpiperazin-1-yl CH₃ C₂H₅ B48 Piperazin-1-yl CH₃ C₂H₅ B49 CH₃ ClC₂H₅ B50 n-C₂H₅ Cl C₂H₅ B51 n-C₃H₇ Cl C₂H₅ B52 CF₃ Cl C₂H₅ B53 CHF₂ ClC₂H₅ B54 CH₂CF₃ Cl C₂H₅ B55 OCH₃ Cl C₂H₅ B56 OCH₂—CH₃ Cl C₂H₅ B57 OCF₃Cl C₂H₅ B58 OCH₂—CF₃ Cl C₂H₅ B59 Phenyl Cl C₂H₅ B60 Phenoxy Cl C₂H₅ B61Benzyl Cl C₂H₅ B62 Cl Cl C₂H₅ B63 Br Cl C₂H₅ B64 I Cl C₂H₅ B65 NH₂ ClC₂H₅ B66 NH-Phenyl Cl C₂H₅ B67 CN Cl C₂H₅ B68 NH-Benzyl Cl C₂H₅ B694-cyanophenyl Cl C₂H₅ B70 4-Morpholinyl Cl C₂H₅ B714-Methylpiperazin-1-yl Cl C₂H₅ B72 Piperazin-1-yl Cl C₂H₅ B73 CH₃ Hn-C₄H₉ B74 n-C₂H₅ H n-C₄H₉ B75 n-C₃H₇ H n-C₄H₉ B76 CF₃ H n-C₄H₉ B77 CHF₂H n-C₄H₉ B78 CH₂CF₃ H n-C₄H₉ B79 OCH₃ H n-C₄H₉ B80 OCH₂—CH₃ H n-C₄H₉ B81OCF₃ H n-C₄H₉ B82 OCH₂—CF₃ H n-C₄H₉ B83 Phenyl H n-C₄H₉ B84 Phenoxy Hn-C₄H₉ B85 Benzyl H n-C₄H₉ B86 Cl H n-C₄H₉ B87 Br H n-C₄H₉ B88 I Hn-C₄H₉ B89 NH₂ H n-C₄H₉ B90 NH-Phenyl H n-C₄H₉ B91 CN H n-C₄H₉ B92NH-Benzyl H n-C₄H₉ B93 4-cyanophenyl H n-C₄H₉ B94 4-Morpholinyl H n-C₄H₉B95 4-Methylpiperazin-1-yl H n-C₄H₉ B96 Piperazin-1-yl H n-C₄H₉ B97 CH₃CH₃ n-C₄H₉ B98 n-C₂H₅ CH₃ n-C₄H₉ B99 n-C₃H₇ CH₃ n-C₄H₉ B100 CF₃ CH₃n-C₄H₉ B101 CHF₂ CH₃ n-C₄H₉ B102 CH₂CF₃ CH₃ n-C₄H₉ B103 OCH₃ CH₃ n-C₄H₉B104 OCH₂—CH₃ CH₃ n-C₄H₉ B105 OCF₃ CH₃ n-C₄H₉ B106 OCH₂—CF₃ CH₃ n-C₄H₉B107 Phenyl CH₃ n-C₄H₉ B108 Phenoxy CH₃ n-C₄H₉ B109 Benzyl CH₃ n-C₄H₉B110 Cl CH₃ n-C₄H₉ B111 Br CH₃ n-C₄H₉ B112 I CH₃ n-C₄H₉ B113 NH₂ CH₃n-C₄H₉ B114 NH-Phenyl CH₃ n-C₄H₉ B115 CN CH₃ n-C₄H₉ B116 NH-Benzyl CH₃n-C₄H₉ B117 4-cyanophenyl CH₃ n-C₄H₉ B118 4-Morpholinyl CH₃ n-C₄H₉ B1194-Methylpiperazin-1-yl CH₃ n-C₄H₉ B120 Piperazin-1-yl CH₃ n-C₄H₉ B121CH₃ Cl n-C₄H₉ B122 n-C₂H₅ Cl n-C₄H₉ B123 n-C₃H₇ Cl n-C₄H₉ B124 CF₃ Cln-C₄H₉ B125 CHF₂ Cl n-C₄H₉ B126 CH₂CF₃ Cl n-C₄H₉ B127 OCH₃ Cl n-C₄H₉B128 OCH₂—CH₃ Cl n-C₄H₉ B129 OCF₃ Cl n-C₄H₉ B130 OCH₂—CF₃ Cl n-C₄H₉ B131Phenyl Cl n-C₄H₉ B132 Phenoxy Cl n-C₄H₉ B133 Benzyl Cl n-C₄H₉ B134 Cl Cln-C₄H₉ B135 Br Cl n-C₄H₉ B136 I Cl n-C₄H₉ B137 NH₂ Cl n-C₄H₉ B138NH-Phenyl Cl n-C₄H₉ B139 CN Cl n-C₄H₉ B140 NH-Benzyl Cl n-C₄H₉ B1414-cyanophenyl Cl n-C₄H₉ B142 4-Morpholinyl Cl n-C₄H₉ B1434-Methylpiperazin-1-yl Cl n-C₄H₉ B144 Piperazin-1-yl Cl n-C₄H₉

Table 297

Compounds of the formulae Id, Ie and If, in which X¹ is CH and thecombination of Z, Q and R^(a) for a compound in each case corresponds toone line of Table C.

Table 298

Compounds of the formulae Id, Ie and If, in which X¹ is N and thecombination of Z, Q and R^(a) for a compound in each case corresponds toone line of Table C.

TABLE C No. Z Q R^(a) C1 O CH₂ C₂H₅ C2 NH CH₂ C₂H₅ C3 CH₂ CH₂ C₂H₅ C4covalent bond CH₂ C₂H₅ C5 O CH₂CH₂ C₂H₅ C6 NH CH₂CH₂ C₂H₅ C7 CH₂ CH₂CH₂C₂H₅ C8 covalent bond CH₂CH₂ C₂H₅ C9 O CH₂ C₄H₉ C10 NH CH₂ C₄H₉ C11 CH₂CH₂ C₄H₉ C12 covalent bond CH₂ C₄H₉ C13 O CH₂CH₂ C₄H₉ C14 NH CH₂CH₂ C₄H₉C15 CH₂ CH₂CH₂ C₄H₉ C16 covalent bond CH₂CH₂ C₄H₉

Particular examples are the following compounds, their N-oxides andpharmaceutical acceptable salts:

-   -   2-butyl-5-(4-phenylpyridin-3-ylamino)isoindolin-1-one    -   2-butyl-5-(5-phenylpyridin-3-ylamino)isoindolin-1-one    -   2-butyl-5-(4-phenylpyridin-3-yloxy)isoindolin-1-one    -   2-butyl-7-chloro-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[5-(piperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[2-chloro-5-(piperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-[(5-chloropyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[5-(morpholin-4-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[2-chloro-5-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-4-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-one        trifluoroacetate    -   2-butyl-5-[(5-phenylpyridin-3-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one        trifluoroacetate    -   2-butyl-6-[(5-phenylpyridin-3-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-one        trifluoroacetate    -   2-butyl-6-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-one        trifluoroacetate    -   2-butyl-5-[(5-phenylpyridin-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-(quinolin-3-ylamino)-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-(quinoxalin-2-ylamino)-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-(6-phenyl-pyrazin-2-ylamino)-2,3-dihydro-isoindol-1-one    -   2-butyl-5-(5-phenylpyridin-3-yl)-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[2-chloro-5-(piperazin-1-yl)pyridine-3-yl]oxy}-3,4-dihydroisoquinolin-1(2H)-one    -   2-[(2-butyl-1-oxo-2,3-dihydro-1H-isoindol-5-yl)amino]-6-chloro-4-(trifluoromethyl)pyridine-3-carbonitrile    -   2-butyl-5-[(2-chloropyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one    -   2-butyl-5-{[2-chloro-5-(4-methylpiperazin-1-yl)pyridine-3-yl]oxy}-3,4-dihydroisoquinolin-1(2H)-one    -   2-(2-methoxyethyl)-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one        and    -   2-(2-methoxyethyl)-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one.

Compounds of formula I can principally prepared by the reactionsoutlined in scheme 1 or scheme 2.

In scheme 1 the variables R^(a), Q, X¹, X², X³, X⁴, Y¹, Y², Y³ and Y⁴are defined as described above. Z is O, S or NR^(Zc). LG represents aleaving group, which can be replaced by any nucleophilic group. Examplesof leaving groups are halogen, such as bromine or iodine or haloalkyl-or arylsulfonates, such as mesylate, tosylate and triflate. According toscheme 1 or scheme 2, the compound II and IV, respectively, is reactedwith compound III to form compound I under the condition of anucleophilic substitution reaction, see e.g. J. March, Advanced OrganicChemistry, fourth edition, Wiley-Interscience, New York, 1992, page 293ff. and the literature cited therein. As it is well known to a personskilled in the art, the addition of a base (auxiliary base) can bebeneficial. Examples of bases includes inorganic bases, e.g. alkalimetalhydroxides or alkalimetal carbonates, such as NaOH, K₂CO₃, CsCO₃, KOHand also organic bases like tertiary amines, e.g. triethylamin,1,8-diazabicyclo[5.4.0]undec-7-en (DBU) or1,5-diazabicyclo[4.3.0]non-5-en (DBN). Furthermore, the addition of acatalyst can also be beneficial. Examples of catalyst are transitionmetal catalyst, such as palladium or platinum catalyst. Ligands such as2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) or2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) mayimprove the activity of the catalyst [Journal of the American ChemicalSociety 116(13), 5969-5970 (1994)].

The compounds, wherein Z is a covalent bond or CR^(Za)R^(Zb), can beprepared by Suzuki cross-coupling reaction between the correspondingboronic ester and the corresponding bromide (s. JACS 2007, 129(6),1486-7). The boronic acid is introducible as its pinacol ester protectedform, by reaction with bis(pinacolato)diboron and catalysis usingPdCl2.dppf in the presence of potassium acetate (s. J. Med. Chem. 2009,52(19), 6097-106).

Compounds of the formula I, wherein Z is S(O) or S(O)₂, can be preparedfrom the compounds of the formula I, wherein Z is S by standardoxidation methods, as described e.g. in WO 2006/058753.

The N-oxides may be prepared from the compounds of formula I accordingto conventional oxidation methods, for example by treating saidcompounds with an organic peracid, such as metachloroperbenzoic acid or3-chloroperbenzoic acid [Journal of Medicinal Chemistry 38(11),1892-1903 (1995), WO 03/64572]; or with inorganic oxidizing agents, suchas hydrogen peroxide [cf. Journal of Heterocyclic Chemistry 18 (7),1305-1308 (1981)] or oxone [cf. Journal of the American Chemical Society123(25), 5962-5973 (2001)]. The oxidation may lead to pure mono-N-oxidesor to a mixture of different N-oxides, which can be separated byconventional methods, such as chromatography.

The reactions are usually performed in an organic solvent, includingaprotic organic solvent, e.g. substituted amides, lactames and ureas,such as dimethylformamide, dimethylacetamide, N-methylpyrrolidone,tetramethyl urea, cyclic ethers such as dioxane, tetrahydrofurane,halogenated hydrocarbons, such as dichloromethane, and mixtures thereofas well as mixtures thereof with C₁-C₆-alkanols and/or water.

The reactions described above will be usually performed at temperaturesranging from −10° C. to 250° C., depending on the reactivity of the usedcompounds. Heating devices, such as microwaves or oil bath, can be used.

The utility of the compounds in accordance with the present invention asmodulators of metabotropic glutamate receptor activity, in particularmGlu2 activity, may be demonstrated by methodology known in the art. Thecompounds of the present invention can be tested e.g. by evaluatingintracellular Ca²⁺ concentrations in cells permanently expressing humanmGlu receptor, the rat glutamate transporter rGLAST and the Galpha16subunit of the G-protein complex under standard conditions in afluorometric imaging plate reader (FLIPR, Molecular Devices, Union City,Calif. 94587, USA) by measuring the response of the cells to a testcompound in the absence of presence of glutamate. The FLIPR assay is acommon functional assay to monitor native or recombinant Galphaq-coupledreceptors, and native or recombinant receptors normally linked to otherG-protein signalling cascades, which are coupled to calcium throughco-expression of an alpha subunit of a promiscuous or chimericG-protein. In the assay the increase of intracellular calcium ismeasured through a calcium-dependent fluorescent dye (e.g. Fluo-4 AM) inthe FLIPR instrument.

For the purpose of the present study, a cell line permanently expressinga human mGlu receptor, such as the mGlu2 receptor, the rat glutamatetransporter rGLAST and the GalphaG16 may be generated by transfection asdescribed in the examples. For selection of a suitable cell clone andalso the subsequent measurements, the selected clone the cells will beplated on suitable multiwell plates in a suitable medium (e.g. DMEMGlutamax (GIBCO #21885-025)/10% dialyzed FCS). Cells may be selected bygentamycin treatment as described in the examples. Cells will then beloaded with a suitable Ca²⁺ sensitive fluorescence dye, e.g. with 2 μMFluo-4 AM (Molecular Probes, F14201). Cells will then be washed with asuitable buffer (e.g. HEPES) and the thus treated plates will bemeasured in a fluorometric imaging plate reader (e.g. FLIPR, MolecularDevices, Union City, Calif. 94587, USA).

The compounds of the present invention were tested in theabove-described FLIPR assay using the selected cell clone. Increasedintracellular calcium levels were quantified following addition of testcompound (agonism), as well as following addition of a submaximalconcentration of glutamate (potentiation).

For the determination of the effect of the test compound by itself(agonism) or by increasing the response to a submaximal concentration(e.g. 1 μM) of glutamate (potentiation), the resulting signal isdetermined by subtraction of the background fluorescence from themaximal fluorescent peak height of the respective response. In the FLIPRinstrument the compound is given to the cell and its fluorescenceresponse quantified by the FLIPR instrument (agonism). The concentrationat which the compound exerts half its maximal effect is named the‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced bythe test substance is normalized to the maximal effect exerted by 100 μMglutamate (set at 100%).

After addition of the test compound to the plate, a submaximalconcentration of glutamate (e.g. 1 μM glutamate) will be added. Apotentiator enhances the response of the receptor to glutamate. Theresponse to glutamate in the presence of test compound is quantified.The concentration at which the test compound is able to exert half itsmaximal potentiation effect to glutamate is named the ‘EC₅₀’. Themaximal response to the submaximal concentration of glutamate (e.g. 1micromolar glutamate) in the presence of test compound is normalized tothe maximal effect exerted by 100 micromolar glutamate (set at 100%).Least squares curve fitting with a four-parameter equation is thenapplied to the resulting dose-response curve to determine the resultingEC₅₀ values (Graph Pad Prism).

A control cell line, HEK293 cells expressing permanently rGLAST andGalpha16 was also plated to a multiwell plate for parallel testing toverify specificity of the test compound for mGlu2 receptor agonism orpotentiation.

The compounds of the invention can be further characterized bymeasurement of their efficacy and potency to inhibit forskolin-inducedcAMP levels in these cells on their own (agonism) or to potentiate theeffect of glutamate (potentiation). Cyclic AMP levels were quantifiedusing Alphascreen technology (PerkinElmer Life and Analytical Sciences,710 Bridgeport Avenue, Shelton, Conn. USA) as described by themanufacturer for determining the effects of Galphai coupled receptors.

The concentration at which a compound exerts half its maximal effect isnamed the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effectinduced by the test substance is normalized to the maximal effectexerted by 100 μM glutamate (100%). Least squares curve fitting with afour-parameter equation is then applied to the resulting dose-responsecurve to determine the resulting EC₅₀ values (Graph Pad Prism).

In particular, the compounds of the following examples had activity inpotentiating the mGlu2 receptor in the aforementioned assays, generallywith an EC₅₀ of not more than about 10 μM. Preferred compounds withinthe present invention had activity in potentiating the mGlu2 receptor inthe aforementioned assays with an EC₅₀ of less than 1 μM, in particularless than 0.5 μM, more preferably of at most 0.2 μM, of at most 0.1 μM.Such a result is indicative of the intrinsic activity of the compoundsin use as positive modulators of mGlu2 receptor activity.

As stated above, the compounds of the present invention are positivemodulators of metabotropic glutamate (mGluR) receptor function, inparticular they are positive modulators of mGlu2 receptors. Thus, thecompounds of the present invention can be used for treating, preventing,ameliorating, controlling or reducing the risk of a variety ofneurological and psychiatric disorders associated with glutamatedysfunction, including one or more of the following conditions ordiseases: acute neurological and psychiatric disorders, such as cerebraldeficits subsequent to cardiac bypass surgery and grafting, stroke,cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia,cardiac arrest, hypoglycemic neuronal damage, dementia (includingAIDS-induced dementia), Alzheimer's disease, Huntington's Chorea,amyotrophic lateral sclerosis, ocular damage, retinopathy, cognitivedisorders, idiopathic and drug-induced Parkinson's disease, muscularspasms and disorders associated with muscular spasticity includingtremors, epilepsy, convulsions, migraine (including migraine headache),urinary incontinence, disorders associated with substance tolerance,disorders associated with substance withdrawal (including substancessuch as opiates, nicotine, tobacco products, alcohol, benzodiazepines,cocaine, sedatives, hypnotics, etc.), psychosis, schizophrenia, anxiety(including generalized anxiety disorder, panic disorder, and obsessivecompulsive disorder), mood disorders (including depression, mania,bipolar disorders), trigeminal neuralgia, hearing loss, tinnitus,macular degeneration of the eye, emesis, brain edema, pain (includingacute and chronic pain states, severe pain, intractable pain,neuropathic pain, and post-traumatic pain), tardive dyskinesia, sleepdisorders (including narcolepsy), attention deficit/hyperactivitydisorder, and conduct disorder.

Of the disorders above, the treatment of schizophrenia, anxiety,depression, substance-related disorders, migraine, and epilepsy are ofparticular importance.

Therefore, the present invention relates to a method for treating amedical disorder, selected from neurological and psychiatric disordersassociated with glutamate dysfunction, said method comprisingadministering an effective amount of at least one compound of thepresent invention to a subject in need thereof.

The compounds of the present invention frequently show an affinitytowards the serotonin 5HT_(2A) receptor. In particular the compounds ofthe present invention are antagonist of the serotonin 5HT_(2A) receptor.Preferred compounds of the present invention have binding constantsKi(5HT_(2A)) below 1 μM, in particular of at most 0.5 μM, morepreferably at most 250 nM or especially at most 100 nM. Thus thecompounds of the present invention are particularly useful for treatingthe above mentioned disorders, in particular psychiatric disorders, suchas schizophrenia, psychosis, cognitive disorders, drug abuse (i.e.disorders associated with substance tolerance, disorders associated withsubstance withdrawal (including substances, such as opiates, nicotine,tobacco products, alcohol, benzodiazepines, cocaine, sedatives,hypnotics, etc.), anxiety (including generalized anxiety disorder, panicdisorder, and obsessive compulsive disorder). The affinity towards the5HT2A receptor as well as the antagonistic action can be determined byroutine screening techniques, a skilled person is familiar with (forreviews see e.g. D. E. Nichols, Halocinogens, in Pharmacology &Therapeutics 101 (2004) 131-181, J. A. Lieberman et al. Biol. Psychiatry44 (1998) 1099-1117, S. Miyamoto et al., Mol. Psychiatry. 10 (2005),79-104).

The subject treated in the present methods is generally a mammal,preferably a human being, male or female, in whom potentiation ofmetabotropic glutamate receptor activity is desired. The term“therapeutically effective amount” means the amount of the subjectcompound that will elicit the biological or medical response of atissue, system, animal or human that is being sought by the researcher,veterinarian, medical doctor or other clinician. It is recognized thatone skilled in the art may affect the neurological and psychiatricdisorders by treating a patient presently afflicted with the disordersor by prophylactically treating a patient afflicted with the disorderswith an effective amount of the compound of the present invention. Asused herein, the terms “treatment” and “treating” refer to allprocesses, wherein there may be a slowing, interrupting, arresting,controlling, or stopping of the progression of the neurological andpsychiatric disorders described herein, but does not necessarilyindicate a total elimination of all disorder symptoms, as well as theprophylactic therapy of the mentioned conditions, particularly in apatient who is predisposed to such disease or disorder. The term“composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term inrelation to pharmaceutical composition, is intended to encompass aproduct comprising the active ingredient(s), and the inert ingredient(s)that make up the carrier, as well as any product which results, directlyor indirectly, from combination, complexation or aggregation of any twoor more of the ingredients, or from dissociation of one or more of theingredients, or from other types of reactions or interactions of one ormore of the ingredients. Accordingly, the pharmaceutical compositions ofthe present invention encompass any composition made by admixing acompound of the present invention and a pharmaceutically acceptablecarrier. By “pharmaceutically acceptable” it is meant the carrier,diluent or excipient must be compatible with the other ingredients ofthe formulation and not deleterious to the recipient thereof.

The terms “administration of and or “administering a” compound should beunderstood to mean providing a compound of the invention or a prodrug ofa compound of the invention to the individual in need of treatment.

A preferred embodiment of the present invention provides a method fortreating schizophrenia, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a N-oxide and/ora pharmaceutically acceptable salt thereof. In another preferredembodiment, the present invention provides a method for preventing ortreating anxiety, comprising: administering to a patient in need thereofan effective amount of a compound of formula I, a tautomer and/or apharmaceutically acceptable salt thereof. Particularly preferred anxietydisorders are generalized anxiety disorder, panic disorder, andobsessive compulsive disorder.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, comprising: administering to apatient in need thereof an effective amount of a compound of formula I,a tautomer and/or a pharmaceutically acceptable salt thereof. In anotherpreferred embodiment the present invention provides a method fortreating migraine, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. In yet anotherpreferred embodiment, the present invention provides a method fortreating epilepsy, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof.

Of the neurological and psychiatric disorders associated with glutamatedysfunction which are treated according to the present invention, thetreatment of schizophrenia, anxiety, depression, migraine,substance-related disorders, especially substance dependence, substancetolerance, substance withdrawal, and epilepsy are particularlypreferred. Particularly preferred anxiety disorders are generalizedanxiety disorder, panic disorder, and obsessive compulsive disorder.

Thus, in a preferred embodiment, the present invention provides a methodfor treating schizophrenia, comprising: administering to a patient inneed thereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. At present, thefourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) (1994, American Psychiatric Association, Washington,D.C.), provides a diagnostic tool including schizophrenia and otherpsychotic disorders. These include: disorders having psychotic symptomsas the defining feature. The term psychotic refers to delusions,prominent hallucinations, disorganized speech, disorganized or catatonicbehavior. The disorder includes: paranoid, disorganized, catatonic,undifferentiated, and residual schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition, substance-induced psychotic disorder, and psychotic disordernot otherwise specified. The skilled artisan will recognize that thereare alternative nomenclatures, nosologies, and classification systemsfor neurological and psychiatric disorders, and particularschizophrenia, and that these systems evolve with medical scientificprogress. Thus, the term “schizophrenia” is intended to include likedisorders that are described in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating anxiety, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. At present, thefourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) (1994, American Psychiatric Association, Washington,D.C.), provides a diagnostic tool including anxiety and relateddisorders. These include: panic disorder with or without agoraphobia,agoraphobia without history of panic disorder, specific phobia, socialphobia, obsessive-compulsive disorder, post-traumatic stress disorder,acute stress disorder, generalized anxiety disorder, anxiety disorderdue to a general medical condition, substance-induced anxiety disorderand anxiety disorder not otherwise specified. As used herein the term“anxiety” includes treatment of those anxiety disorders and relateddisorder as described in the DSM-IV. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies, and classificationsystems for neurological and psychiatric disorders, and particularanxiety, and that these systems evolve with medical scientific progress.Thus, the term “anxiety” is intended to include like disorders that aredescribed in other diagnostic sources.

In another preferred embodiment, the present invention provides a methodfor treating depression, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a N-oxide and/ora pharmaceutically acceptable salt thereof. At present, the fourthedition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV) (1994, American Psychiatric Association, Washington, D.C.),provides a diagnostic tool including depression and related disorders.Depressive disorders include, for example, single episodic or recurrentmajor depressive disorders, and dysthymic disorders, depressiveneurosis, and neurotic depression; melancholic depression includinganorexia, weight loss, insomnia and early morning waking, andpsychomotor retardation; atypical depression (or reactive depression)including increased appetite, hypersomnia, psychomotor agitation orirritability, anxiety and phobias; seasonal affective disorder; orbipolar disorders or manic depression, for example, bipolar I disorder,bipolar II disorder and cyclothymic disorder. As used herein the term“depression” includes treatment of those depression disorders andrelated disorder as described in the DSM-1V.

In another preferred embodiment, the present invention provides a methodfor treating substance-related disorders, especially substancedependence, substance abuse, substance tolerance, and substancewithdrawal, comprising: administering to a patient in need thereof aneffective amount of a compound of formula I, a tautomer and/or apharmaceutically acceptable salt thereof. At present, the fourth editionof the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV)(1994, American Psychiatric Association, Washington, D.C.), provides adiagnostic tool including disorders related to taking a drug of abuse(including alcohol), to the side effects of a medication, and to toxinexposure. Substances include alcohol, amphetamine and similarly actingsympathomimetics, caffeine, cannabis, cocaine, hallucinogens, inhalants,nicotine, opioids, phencyclidine (PCP) or similarly actingarylcyclohexylamines, and sedatives, hypnotics, or anxiolytics. Also,polysubstance dependence and other unknown substance-related disordersare included. The skilled artisan will recognize that there arealternative nomenclatures, nosologies, and classification systems forneurological and psychiatric disorders, and particular substance-relateddisorders, and that these systems evolve with medical scientificprogress. Thus, the term “substance-related disorder” is intended toinclude like disorders that are described in other diagnostic sources.

In another preferred embodiment the present invention provides a methodfor treating migraine, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. In one of theavailable sources of diagnostic tools, Dorland's Medical Dictionary(23'rd Ed., 1982, W. B. Saunders Company, Philadelphia, Pa.), migraineis defined as a symptom complex of periodic headaches, usually temporaland unilateral, often with irritability, nausea, vomiting, constipationor diarrhea, and photophobia. As used herein the term “migraine includesthese periodic headaches, both temporal and unilateral, the associatedirritability, nausea, vomiting, constipation or diarrhea, photophobia,and other associated symptoms. The skilled artisan will recognize thatthere are alternative nomenclatures, nosologies, and classificationsystems for neurological and psychiatric disorders, including migraine,and that these systems evolve with medical scientific progress.

In another preferred embodiment, the present invention provides a methodfor treating epilepsy, comprising: administering to a patient in needthereof an effective amount of a compound of formula I, a tautomerand/or a pharmaceutically acceptable salt thereof. At present, there areseveral types and subtypes of seizures associated with epilepsy,including idiopathic, symptomatic, and cryptogenic. These epilepticseizures can be focal (partial) or generalized. They can also be simpleor complex. Epilepsy is described in the art, such as Epilepsy: Acomprehensive textbook. Ed. by Jerome Engel, Jr. and Timothy A. Pedley(Lippincott-Raven, Philadelphia, 1997). At present, the InternationalClassification of Diseases, Ninth Revision, (ICD-9) provides adiagnostic tool including epilepsy and related disorders. These include:generalized nonconvulsive epilepsy, generalized convulsive epilepsy,petit mal status epilepticus, grand mal status epilepticus, partialepilepsy with impairment of consciousness, partial epilepsy withoutimpairment of consciousness, infantile spasms, epilepsy partialiscontinua, other forms of epilepsy, epilepsy, unspecified, NOS. As usedherein the term “epilepsy” includes these all types and subtypes. Theskilled artisan will recognize that there are alternative nomenclatures,nosologies, and classification systems for neurological and psychiatricdisorders, including epilepsy, and that these systems evolve withmedical scientific progress.

In the treatment, prevention, control, amelioration, or reduction ofrisk of conditions which require potentiation of metabotorpic glutamatereceptor activity an appropriate dosage level will generally be about0.01 to 500 mg per kg patient body weight per day which can beadministered in single or multiple doses. Preferably, the dosage levelwill be about 0.1 to about 250 mg/kg per day; more preferably about 0.5to about 100 mg/kg per day. A suitable dosage level may be about 0.01 to250 mg/kg per day, about 0.05 to 100 mg/kg per day, or about 0.1 to 50mg/kg per day. Within this range the dosage may be 0.05 to 0.5, 0.5 to 5or 5 to 50 mg/kg per day. For oral administration, the compositions arepreferably provided in the form of tablets containing 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 5.0, 10.0, 15.0,20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0, 500.0,600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient for the symptomatic adjustment of the dosage to the patientto be treated. The compounds may be administered on a regimen of 1 to 4times per day, preferably once or twice per day. When treating,preventing, controlling, ameliorating, or reducing the risk ofneurological and psychiatric disorders associated with glutamatedysfunction or other diseases for which compounds of the presentinvention are indicated, generally satisfactory results are obtainedwhen the compounds of the present invention are administered at a dailydosage of from about 0.1 milligram to about 100 milligram per kilogramof animal body weight, preferably given as a single daily dose or individed doses two to six times a day, or in sustained release form. Formost large mammals, the total daily dosage is from about 1.0 milligramsto about 1000 milligrams, preferably from about 1 milligram to about 50milligrams, hi the case of a 70 kg adult human, the total daily dosewill generally be from about 7 milligrams to about 350 milligrams. Thisdosage regimen may be adjusted to provide the optimal therapeuticresponse. It will be understood, however, that the specific dose leveland frequency of dosage for any particular patient may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

The compounds according to the present invention are further useful in amethod for the prevention, treatment, control, amelioration, orreduction of risk of the aforementioned diseases, disorders andconditions in combination with other agents, including an mGluR agonist.

The term “potentiated amount” refers to an amount of an mGluR agonist,that is, the dosage of agonist which is effective in treating theneurological and psychiatric disorders described herein whenadministered in combination with an effective amount of a compound ofthe present invention. A potentiated amount is expected to be less thanthe amount that is required to provide the same effect when the mGluRagonist is administered without an effective amount of a compound of thepresent invention.

A potentiated amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of conventionaltechniques and by observing results obtained under analogouscircumstances. In determining a potentiated amount, the dose of an mGluRagonist to be administered in combination with a compound of formula I,a number of factors are considered by the attending diagnostician,including, but not limited to: the mGluR agonist selected to beadministered, including its potency and selectivity; the compound offormula Ito be coadministered; the species of mammal; its size, age, andgeneral health; the specific disorder involved; the degree ofinvolvement or the severity of the disorder; the response of theindividual patient; the modes of administration; the bioavailabilitycharacteristics of the preparations administered; the dose regimensselected; the use of other concomitant medication; and other relevantcircumstances.

A potentiated amount of an mGluR agonist to be administered incombination with an effective amount of a compound of formula I isexpected to vary from about 0.1 milligram per kilogram of body weightper day (mg/kg/day) to about 100 mg/kg/day and is expected to be lessthan the amount that is required to provided the same effect whenadministered without an effective amount of a compound of formula I.Preferred amounts of a co-administered mGlu agonist are able to bedetermined by one skilled in the art. The compounds of the presentinvention may be used in combination with one or more other drugs in thetreatment, prevention, control, amelioration, or reduction of risk ofdiseases or conditions for which compounds of Formula I or the otherdrugs may have utility, where the combination of the drugs together aresafer or more effective than either drug alone. Such other drug(s) maybe administered, by a route and in an amount commonly used therefore,contemporaneously or sequentially with a compound of Formula I. When acompound of formula I is used contemporaneously with one or more otherdrugs, a pharmaceutical composition in unit dosage form containing suchother drugs and the compound of formula I is preferred. However, thecombination therapy may also include therapies in which the compound offormula I and one or more other drugs are administered on differentoverlapping schedules. It is also contemplated that when used incombination with one or more other active ingredients, the compounds ofthe present invention and the other active ingredients may be used inlower doses than when each is used singly. Accordingly, thepharmaceutical compositions of the present invention include those thatcontain one or more other active ingredients, in addition to a compoundof formula I. The above combinations include combinations of a compoundof the present invention not only with one other active compound, butalso with two or more other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly usedtherefore, contemporaneously or sequentially with a compound of thepresent invention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is preferred. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the compound of the presentinvention to the second active ingredient may be varied and will dependupon the effective dose of each ingredient. Generally, an effective doseof each will be used. Thus, for example, when a compound of the presentinvention is combined with another agent, the weight ratio of thecompound of the present invention to the other agent will generallyrange from about 1000:1 to about 1:1000, preferably about 200:1 to about1:200. Combinations of a compound of the present invention and otheractive ingredients will generally also be within the aforementionedrange, but in each case, an effective dose of each active ingredientshould be used. In such combinations the compound of the presentinvention and other active agents may be administered separately or inconjunction. In addition, the administration of one element may be priorto, concurrent to, or subsequent to the administration of otheragent(s).

The compounds of the present invention may be administered byconventional routes of administration, including parenteral (e.g.,intramuscular, intrapentoneal, intravenous, ICV, intracisternalinjection or infusion, subcutaneous injection, or implant), byinhalation spray, nasal, vaginal, rectal, sublingual, or topical routesof administration.

The compounds of the present invention may be formulated alone ortogether with further active compounds, in suitable dosage unitformulations containing conventional non-toxic pharmaceuticallyexcipients. Excipients can be solid, semisolid or liquid materials whichserve as vehicles, carriers or medium for the active compound. Suitableexcipients are listed in the specialist medicinal monographs. Inaddition, the formulations can comprise pharmaceutically acceptablecarriers or customary auxiliary substances, such as glidants; wettingagents; emulsifying and suspending agents; preservatives; antioxidants;antiirritants; chelating agents; coating auxiliaries; emulsionstabilizers; film formers; gel formers; odor masking agents; tastecorrigents; resin; hydrocolloids; solvents; solubilizers; neutralizingagents; diffusion accelerators; pigments; quaternary ammonium compounds;refatting and overfatting agents; raw materials for ointments, creams oroils; silicone derivatives; spreading auxiliaries; stabilizers;sterilants; suppository bases; tablet auxiliaries, such as binders,fillers, glidants, disintegrants or coatings; propellants; dryingagents; opacifiers; thickeners; waxes; plasticizers and white mineraloils. A formulation in this regard is based on specialist knowledge asdescribed, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fürPharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliarysubstances for pharmacy, cosmetics and related fields], 4^(th) edition,Aulendorf: ECV-Editio-Kantor-Verlag, 1996.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugar-coated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more excipients.

The following examples are intended for further illustration of thepresent invention.

PREPARATION EXAMPLES

Abbreviations used in the Examples that follow are: Ac acetate, BINAP2,2′-bis(diphenylphosphino)-1,1′-binaphthyl, dba dibenzylideneacetone,HPLC high performance liquid chromatography, NMP N-methylpyrrolidone.

Example 1 2-butyl-5-(4-phenylpyridin-3-ylamino)isoindolin-1-one

3-Bromo-4-phenylpyridine (125 mg, 0.534 mmol) was added to a suspensionof 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) (33 mg, 0.053mmol) and tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) (49 mg,0.053 mmol) in toluene (5 mL). 5-Amino-2-butylisoindolin-1-one (120 mg,0.587 mmol) and sodium tert-butoxide (128 mg, 1.335 mmol) were added andthe mixture was stirred and heated in the microwave (120° C., 300 W, 75min). Water and ethyl acetate were added, the organic layer wasseparated and the aqueous layer was extracted with ethyl acetate. Thecombined organic layers were washed with water and dried over MgSO₄.Purification by flash chromatography (dichloromethane/methanol, gradient1-5% methanol) provided2-butyl-5-(4-phenylpyridin-3-ylamino)isoindolin-1-one (56 mg, 46%).ESI-MS [M+H]⁺=358.2.

Example 2 2-butyl-5-(5-phenylpyridin-3-ylamino)isoindolin-1-one

5-Bromo-2-butylisoindolin-1-one (71.6 mg, 0.267 mmol),5-phenylpyridin-3-amine (50.0 mg, 0.294 mmol) and Cs₂CO₃ (217.0 mg,0.668 mmol) were added to suspension of2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos) (12.7 mg,0.027 mmol) and palladium acetate (PdOAc₂) (8.0 mg, 0.040 mmol) intoluene (2 mL). The mixture was stirred and heated in the microwave(120° C., 300 W, 60 min). Water and ethyl acetate were added. Theorganic layer was separated, the aqueous layer was extracted with ethylacetate and the combined organic layers were dried over MgSO₄.Purification by flash chromatography (dichloromethane/methanol, gradient1-5% methanol) provided2-butyl-5-(5-phenylpyridin-3-ylamino)isoindolin-1-one (53 mg, 54%).ESI-MS [M+H]⁺=358.1.

Example 3 2-butyl-5-(4-phenylpyridin-3-yloxy)isoindolin-1-one

A mixture of 3-bromo-4-phenylpyridine (50 mg, 0.213 mmol),2-butyl-5-hydroxy-isoindolin-1-one (88 mg, 0.427 mmol), Cs₂CO₃ (139 mg,0.427 mmol), CuI (16.3 mg, 0.085 mmol) and2,2,6,6-tetramethyl-3.5-heptanedione (53 μL, 0.256 mmol) in degassedN-methylpyrrolidone (NMP) (2 mL) was stirred and heated in the microwave(220° C., 300 W, 30 min). Two of those reactions were combined, excesswater and ethyl acetate were added. The organic layer was separated andthe aqueous layer was extracted with ethyl acetate. The combined organiclayers were extracted with aqueous HCl (2 M) and the combined extractswere basified with aqueous NaOH (2 M) followed by extraction with ethylacetate. The combined organic layers were washed with water and driedover MgSO₄. Purification by HPLC provided2-butyl-5-(4-phenylpyridin-3-yloxy)isoindolin-1-one (16 mg, 8%).

ESI-MS [M+H]⁺=359.1.

The following examples 4 to 18 have been prepared in a similar way:

Example 42-butyl-7-chloro-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=392.10;

¹H NMR (chloroform-d, 500 MHz): δ ppm 8.56 (d, J=1.8 Hz, 1 H), 8.47 (d,J=2.4 Hz, 1 H), 7.67 (d, J=2.1 Hz, 1 H), 7.55-7.60 (m, 2 H), 7.49 (t,J=7.5 Hz, 2 H), 7.43 (m, 1 H), 6.95-7.04 (m, 2 H), 6.30 (s, 1 H), 4.25(s, 2 H), 3.56 (t, J=7.3 Hz, 2 H), 1.57-1.67 (m, 2 H), 1.37 (m, 2 H),0.94 (t, J=7.3 Hz, 3 H).

Example 52-butyl-5-{[5-(piperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=366.25;

¹H NMR (DMSO-d₆, 500 MHz): δ ppm 8.59 (s, 1 H), 7.88 (d, J=2.1 Hz, 2 H),7.50 (d, J=8.2 Hz, 1 H), 7.17 (s, 1 H), 7.06 (dd, J=8.4, 1.7 Hz, 1 H),6.86-7.02 (m, 1 H), 4.35 (s, 2 H), 2.99-3.14 (m, 4 H), 2.74-2.94 (m, 4H), 1.54 (quin, J=7.3 Hz, 2 H), 1.26 (sxt, J=7.4 Hz, 2 H), 0.89 (t,J=7.3 Hz, 3 H).

Example 62-butyl-5-{[2-chloro-5-(piperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=400.20;

¹H NMR (DMSO-d₆, 500 MHz): δ ppm 8.15 (s, 1 H), 7.77 (d, J=2.7 Hz, 1 H),7.50 (d, J=7.9 Hz, 1 H), 7.20 (d, J=2.4 Hz, 1 H), 7.02-7.09 (m, 2 H),4.34 (s, 2 H), 3.43-3.48 (m, 2 H), 3.01-3.10 (m, 4 H), 2.80 (d, J=4.6Hz, 4 H), 1.54 (quin, J=7.2 Hz, 2 H), 1.27 (dq, J=14.8, 7.3 Hz, 2 H),0.89 (t, J=7.3 Hz, 3 H).

Example 72-butyl-5-[(5-chloropyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=316.10;

¹H NMR (DMSO-d₆, 400 MHz): δ ppm 8.97 (s, 1 H), 8.37 (d, J=2.4 Hz, 1 H),8.11 (d, J=2.0 Hz, 1 H), 7.53-7.64 (m, 2 H), 7.28-7.34 (s, 1 H), 7.15(dd, J=8.3, 2.0 Hz, 1 H), 4.40 (s, 2 H), 3.47 (t, J=7.1 Hz, 2 H), 1.57(quin, J=7.3 Hz, 2 H), 1.29 (dq, J=14.9, 7.3 Hz, 2 H), 0.91 (t, J=7.5Hz, 3 H).

Example 82-butyl-5-{[5-(morpholin-4-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=367.10;

¹H NMR (DMSO-d₆, 400 MHz): δ ppm 8.60 (s, 1 H), 7.93 (d, J=2.4 Hz, 2 H),7.49 (d, J=8.3 Hz, 1 H), 7.19 (s, 1 H), 7.05-7.08 (m, 1 H), 7.02 (t,J=2.3 Hz, 1 H), 4.35 (s, 2 H), 3.72-3.77 (m, 4 H), 3.45 (t, J=7.1 Hz, 2H), 3.11-3.16 (m, 4 H), 1.55 (quin, J=7.2 Hz, 2 H), 1.28 (dq, J=7.6 Hz,2 H), 0.91 (t, J=7.3 Hz, 3 H).

Example 92-butyl-5-{[2-chloro-5-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=414.20;

¹H NMR (DMSO-d₆, 500 MHz): δ ppm 8.21 (s, 1 H), 7.81 (d, J=2.7 Hz, 1 H),7.50 (d, J=7.9 Hz, 1 H), 7.25 (d, J=2.7 Hz, 1 H), 7.03-7.13 (m, 2 H),4.36 (s, 2 H), 3.46 (t, J=7.2 Hz, 2 H), 3.08-3.22 (m, 4 H), 2.37-2.46(m, 4 H), 2.20 (s, 3 H), 1.55 (quin, J=7.2 Hz, 2 H), 1.21-1.35 (m, 2 H),0.91 (t, J=7.5 Hz, 3 H).

Example 102-butyl-5-{[5-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindol-1-one

¹H NMR (DMSO-d₆, 500 MHz): δ=8.63 (s, 1 H), 7.92 (d, 2 H), 7.50 (d,J=8.2 Hz, 1 H), 7.19 (s, 1 H), 7.07 (dd, J=8.4, 1.7 Hz, 1 H), 7.01 (t,J=2.3 Hz, 1 H), 4.36 (s, 2 H), 3.46 (t, J=7.2 Hz, 2 H), 3.07-3.22 (m, 4H), 2.45 (d, J=4.9 Hz, 4 H), 2.22 (s, 3 H), 1.48-1.64 (m, 2 H),1.18-1.35 (m, 2 H), 0.91 (t, J=7.3 Hz, 3 H).

Example 112-butyl-5-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=359.10.

Example 122-butyl-4-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-onetrifluoroacetate

ESI-MS: [M+H]⁺=359.10;

¹H NMR (500 MHz, DMSO) δ ppm 8.80 (s, 1H), 8.49 (s, 1H), 7.92 (t, J=2.1,1H), 7.75 (t, J=10.4, 2H), 7.57-7.39 (m, 5H), 7.23 (dd, J=2.4, 6.4, 1H),4.46 (s, J=46.1, 2H), 3.50 (t, J=7.2, 2H), 1.61-1.50 (m, 2H), 1.32-1.20(m, 2H), 0.87 (t, J=7.4, 3H).

Example 132-butyl-5-[(5-phenylpyridin-3-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-onetrifluoroacetate

ESI-MS: [M+H]⁺=373.20;

¹H NMR (500 MHz, DMSO) δ ppm 8.72 (s, 1H), 8.35 (s, 1H), 7.74 (m, 4H),7.53-7.35 (m, 4H), 7.23 (d, J=8.0, 1H), 3.50 (m, 4H), 2.92 (t, J=6.6,2H), 1.58-1.47 (m, 2H), 1.35-1.23 (m, 2H), 0.89 (t, J=7.4, 3H).

Example 142-butyl-6-[(5-phenylpyridin-3-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-onetrifluoroacetate

ESI-MS: [M+H]⁺=373.20;

¹H NMR (500 MHz, DMSO) δ ppm 8.81 (s, 1H), 8.46 (d, J=2.1, 1H),7.95-7.85 (m, 2H), 7.80-7.72 (m, 2H), 7.47 (m, 3H), 7.08-6.96 (m, 2H),3.47 (dt, J=6.9, 14.5, 4H), 2.93 (t, J=6.5, 2H), 1.56-1.45 (m, 2H),1.34-1.21 (m, 2H), 0.89 (t, J=7.4, 3H).

Example 152-butyl-6-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-onetrifluoroacetate

ESI-MS: [M+H]⁺=359.10;

¹H NMR (500 MHz, DMSO) δ ppm 8.80 (s, 1H), 8.46 (s, 1H), 7.89 (s, 1H),7.74 (d, J=7.2, 2H), 7.64 (d, J=8.2, 1H), 7.53-7.36 (m, 4H), 7.31 (d,J=2.3, 1H), 4.45 (s, 2H), 3.49 (t, J=7.2, 2H), 1.62-1.49 (m, 2H),1.32-1.20 (m, 2H), 0.88 (t, J=7.4, 3H).

Example 162-butyl-5-(6-phenyl-pyrazin-2-ylamino)-2,3-dihydro-isoindol-1-one

ESI-MS: [M+H]⁺=359.10.

Example 17 2-butyl-5-(quinolin-3-ylamino)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=332.10;

¹H NMR (chloroform-d, 500 MHz): δ ppm 8.78 (d, J=2.7 Hz, 1 H), 8.04 (d,J=8.5 Hz, 1 H), 7.85 (d, J=2.4 Hz, 1 H), 7.76 (d, J=7.9 Hz, 1 H), 7.70(d, J=7.9 Hz, 1 H), 7.59 (td, J=7.6, 1.4 Hz, 1 H), 7.50-7.54 (m, 1 H),7.13-7.19 (m, 2 H), 6.53 (br. s., 1 H), 4.32 (s, 2 H), 3.60 (t, J=7.3Hz, 2 H), 1.60-1.68 (m, 2 H), 1.34-1.42 (m, 2 H), 0.95 (t, J=7.5 Hz, 3H).

Example 182-butyl-5-(quinoxalin-2-ylamino)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=333.10;

¹H NMR (DMSO-d₆, 500 MHz): δ ppm 10.29 (s, 1 H), 8.62 (s, 1 H), 8.42 (s,1 H), 7.87-7.93 (m, 2 H), 7.78-7.83 (m, 1 H), 7.63-7.72 (m, 2 H),7.49-7.54 (m, 1 H), 4.49 (s, 2 H), 3.50 (t, J=7.2 Hz, 2 H), 1.59 (quin,J=7.3 Hz, 2 H), 1.30 (sxt, J=7.3 Hz, 2 H), 0.92 ppm (t, J=7.5 Hz, 3 H).

Example 192-(2-methoxyethyl)-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=360.10.

Example 202-butyl-5-[(2-chloropyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one

¹H NMR (DMSO-d₆, 500 MHz): δ=7.98 (m, 1 H), 7.80 (d, 1 H), 7.64 (d, 1H), 7.20 (s, 1 H), 7.16-7.19 (m, 2 H), 6.32 (br. s., 1 H), 4.35 (s, 2H), 3.61 (t, J=7.3 Hz, 2 H), 1.65 (quint, 2 H), 1.39 (m sym., 2 H), 0.96(t, J=7.3 Hz, 3 H).

Example 212-butyl-5-{[2-chloro-5-(piperazin-1-yl)pyridin-3-yl]oxy}-3,4-dihydroisoquinolin-1(2H)-one

ESI-MS: [M+H]⁺=415.20.

Example 222-butyl-5-{[2-chloro-5-(4-methylpiperazin-1-yl)pyridin-3-yl]oxy}-3,4-dihydroisoquinolin-1(2H)-one

ESI-MS: [M+H]⁺=429.20.

Example 232-butyl-5-[(5-phenylpyridin-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one

Dioxane (5 mL) was added to a solution of sodium phosphate (77 mg, 0.365mmol) in water (0.5 ml). 3-(Bromomethyl)-5-phenylpyridine hydrobromide(50 mg, 0.152 mmol, described in BMCL 2001, 11(17), 2345-9),2-butyl-1-oxoisoindolin-5-ylboronic acid (35.4 mg, 0.152 mmol; preparedfrom the corresponding bromide as described in J. Med. Chem. 2009,52(19), 6097-106)), X-Phos (2.90 mg, 6.08 μmol) and Pd₂(dba)₃ (5.57 mg,6.08 μmol) were added and the mixture stirred for 12 h at roomtemperature. The solution was dried in vacuo, the residue solved inwater and extracted with ethyl acetate. The organic phase was dried onNa₂SO₄, filtrated and dried in vacuo. Purification on a column ofsilicagel (eluent 30:1 CH₂Cl₂: NH₃ (2M in EtOH)) afforded 3 mg (6%yield) of Example 23.

ESI-MS: [M+H]⁺=357.10;

¹H NMR (DMSO-d₆, 500 MHz): δ ppm 8.74 (d, J=2.1 Hz, 1 H), 8.54 (d, J=1.8Hz, 1 H), 7.99 (s, 1 H), 7.70 (d, J=7.0 Hz, 2 H), 7.61 (d, J=7.6 Hz, 1H), 7.41-7.55 (m, 5 H), 4.42 (s, 2 H), 4.17 (s, 2 H), 3.48 (t, J=7.2 Hz,2 H), 1.55 (quin, J=7.3 Hz, 2 H), 1.23-1.30 (m, 2 H), 0.89 (t, J=7.3 Hz,3 H).

Example 242-butyl-5-(5-phenylpyridin-3-yl)-2,3-dihydro-1H-isoindol-1-one

ESI-MS: [M+H]⁺=343.10;

As described for Example 23 starting from 3-bromo-5-phenylpyridine (50mg, 0.214 mmol, commercially available) and2-butyl-1-oxoisoindolin-5-ylboronic acid (49.8 mg, 0.214 mmol, s.above). Yield 14% (10 mg).

¹H NMR (500 MHz, DMSO) δ ppm 8.93 (m, 2H), 8.36 (s, 1H), 8.07 (s, 1H),7.96 (d, J=7.9, 1H), 7.86 (d, 2H), 7.81 (d, 1H), 7.55 (t, 2H), 7.53 (t,1H), 4.54 (s, 2H), 3.54 (t, 2H), 1.60 (quin, 2H), 1.30 (sext, 2H), 0.91(t, J=7.4, 3H).

Biological Tests

I Generation of a HEK293 Cell Clones Permanently Expressing mGluReceptors and Functional Evaluation of the Cells

a) mGlu2 Receptor

For the purpose of the present study, a cell line permanently expressingthe human mGlu2 receptor, the rat glutamate transporter rGLAST and thealpha subunit of G16 was generated by transfection. Briefly, HEK293cells were seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶cells in DMEM with glutamax (Invitrogen, GIBCO #21885-025), 10% dialyzedFetal Calf Serum (Invitrogen, Gibco #26400-044), and incubated at 37° C.over night. The following day cells were transfected with Lipofectamine(Invitrogen, Gibco #18324-012) as recommended by the manufacturer, usinglinearized pcDNA3.1 (V5/His)-hmGlu2 receptor (ScaI) and pcDNA3.1Zeo-Ga16 IRES rGLAST (SspI). After transfection the cells were selectedin DMEM Glutamax Medium (Invitrogen, GIBCO #21885-025), containing 10%dialyzed fetal calf serum (FCS; (Invitrogen, Gibco #26400-044),antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 250 μg/ml Zeozin.Single clones were isolated manually and further subcloned by serialdilution.

The function of the mGlu2 receptor was determined by evaluatingintracellular Ca²⁺ concentrations under standard conditions in afluorometric imaging plate reader (FLIPR, Molecular Devices, Union City,Calif. 94587, USA) by measuring the response of the cells to a testcompound. The FLIPR assay is a common functional assay to monitor nativeor recombinant Galphaq-coupled receptors, and native or recombinantreceptors normally linked to other G-protein signalling cascades, whichare coupled to calcium through co-expression of an alpha subunit of apromiscuous or chimeric G-protein. In the assay the increase ofintracellular calcium is measured through a calcium-dependentfluorescent dye (e.g. Fluo-4 AM) in the FLIPR instrument.

For selection of a suitable cell clone and also the subsequentmeasurements of the selected clone, 4×10⁴ cells/well were plated onpoly-D-lysine coated Biocoat-plates multiwell 96 in DMEM Glutamax (GIBCO#21885-025)/10% dialyzed FCS over night. The following day, the mediumwas aspirated and exchanged for glutamate-free DMEM (Gibco #21969-035),without FCS or glutamine, containing 50 μg/ml gentamycin (Gibco #15750).Cells were again incubated over night. Before the measurement, cellswere loaded with 2 μM Fluo-4 AM (Molecular Probes, F14201; stocksolution 1 mM in DMSO) and 0.02% Pluronic F127 (Molecular Probes, P3000;stock solution 10% in DMSO) in DMEM medium (Gibco #21969-035) for 45minutes at 37° C. in a final volume of 100 μl per well. Finally, theplates were washed in a BioTec cell washer with HBSS, containing 20 mMHEPES. The end-volume in each well was 100 μl. The plates weresubsequently measured in a fluorometric imaging plate reader (FLIPR,Molecular Devices, Union City, Calif. 94587, USA).

The compounds of the present invention were tested in theabove-described FLIPR assay using the selected cell clone. Increasedintracellular calcium levels were quantified following addition of testcompound (agonism), as well as following addition of a submaximalconcentration of 1 micromolar (1 μM) glutamate (potentiation).

For the determination of the effect of the test compound by itself(agonism) or by increasing the response to a submaximal concentration(e.g. 1 μM) of glutamate (potentiation), the resulting signal isdetermined by subtraction of the background fluorescence from themaximal fluorescent peak height of the respective response. In the FLIPRinstrument the compound is given to the cell and its fluorescenceresponse quantified by the FLIPR instrument (agonism). The concentrationat which the compound exerts half its maximal effect is named the‘effective concentration 50’ or ‘EC₅₀’. The maximal effect induced bythe test substance is normalized to the maximal effect exerted by 100 μMglutamate (set at 100%).

Ten minutes after addition of the test compound to the plate, 1 μMglutamate is added. A potentiator enhances the response of the receptorto glutamate. The response to glutamate in the presence of test compoundis quantified. The concentration at which the test compound is able toexert half its maximal potentiation effect to glutamate is named the‘EC₅₀’. The maximal response to 1 micromolar glutamate in the presenceof test compound is normalized to the maximal effect exerted by 100 μMglutamate (set at 100%). Least squares curve fitting with afour-parameter equation is then applied to the resulting dose-responsecurve to determine the resulting EC₅₀ values (Graph Pad Prism). Acontrol cell line, HEK293 cells expressing permanently rGLAST andGalpha16 was also plated at 4×10⁴ cells/well for parallel testing toverify specificity of the test compound for mGlu2 receptor agonism orpotentiation. The EC₅₀ values are given in table I.

Highly potent or key compounds were further characterized by measurementof their efficacy and potency to inhibit forskolin-induced cAMP levelsin these cells on their own (agonism) or to potentiate the effect ofglutamate (potentiation). Cyclic AMP levels were quantified usingAlphascreen technology (PerkinElmer Life and Analytical Sciences, 710Bridgeport Avenue, Shelton, Conn. USA) as described by the manufacturerfor determining the effects of Galphai coupled receptors. Theconcentration at which a compound exerts half its maximal effect isnamed the ‘effective concentration 50’ or ‘EC₅₀’. The maximal effectinduced by the test substance is normalized to the maximal effectexerted by 100 μM glutamate (100%). Least squares curve fitting with afour-parameter equation is then applied to the resulting dose-responsecurve to determine the resulting EC₅₀ values (Graph Pad Prism).

The compounds of the following examples had activity in potentiating themGlu2 receptor in the aforementioned assays, generally with an EC₅₀ ofnot more than about 10 μM. Preferred compounds within the presentinvention had activity in potentiating the mGlu2 receptor in theaforementioned assays with an EC₅₀ of less than about 1 μM. Such aresult is indicative of the intrinsic activity of the compounds in useas potentiators of mGlu2 receptor activity.

TABLE I EXAMPLE EC₅₀ ¹⁾ 4 ++ 5 + 6 + 7 ++ 8 +++ 9 ++ 10 + 11 +++ 12 +++13 +++ 14 +++ 15 ++ 16 +++ 17 ++ 18 + 19 ++ 20 + 21 ++ 22 ++ 23 ++ 24 ++¹⁾+++: EC₅₀ < 0.5 μM ++: 0.5 μM ≦ EC₅₀ ≦ 2 μM +: 2 μM < EC₅₀ < 10 μM

b) mGlu3 Receptor

For the purpose of the present study, we generated by transfection acell line permanently expressing the human mGlu3 receptor, the ratglutamate transporter rGLAST and the alpha subunit of G16. Briefly,HEK293 cells were seeded in petri dishes (diameter 15 cm) at a densityof 2×10⁶ cells in DMEM with glutamax (Invitrogen, GIBCO #21885-025), 10%dialyzed Fetal Calf Serum (Invitrogen, Gibco #26400-044), and incubatedat 37° C. over night. The following day cells were transfected withLipofectamine (Invitrogen, Gibco #18324-012) as recommended by themanufacturer, using linearized pcDNA3.1 (V5/His)-hmGlu3 receptor (ScaI)and pcDNA3.1 Zeo-Ga16 IRES rGLAST (SspI). After transfection the cellswere selected in DMEM Glutamax Medium (Invitrogen, GIBCO #21885-025),containing 10% dialyzed fetal calf serum (FCS; (Invitrogen, Gibco#26400-044), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 250μg/ml Zeozin. Single clones were isolated manually and further subclonedby serial dilution. Function was tested with FLIPR as described above.

c) mGlu4 Receptor

For the purpose of the present study, we generated by transfection acell line permanently expressing human mGlu4 receptor, the rat glutamatetransporter rGLAST and the alpha subunit of G15. Briefly, HEK293 cellswere seeded in petri dishes (diameter 15 cm) at a density of 2×10⁶ cellsin DMEM glutamax, 10% dialyzed FCS, and incubated at 37° C. over night.The following day cells were transfected with Lipofectamine (Invitrogen,Karlsruhe, Germany) as recommended by the manufacturer, using linearisedpcDNA3-hmGlu4 (SspI) and pcDNA3.1(+) Hygro-rGLAST IRES Ga15 (SspI).After transfection the cells were cultured in DMEM Glutamax Medium(Invitrogen), containing 10% dialyzed fetal calf serum (FCS;Invitrogen), antibiotic/antimycotic, 800 μg/ml Geneticin (G418) and 150μg/ml Hygromycin, and single clones were isolated manually and subclonedby serial dilution. Function was tested with FLIPR as described above.

d) mGlu7 Receptor

For the purpose of the present study, we generated by transfection acell line permanently expressing human mGlu7a receptor, the ratglutamate transporter rGLAST and the alpha subunit of G15. Briefly,HEK293 cells were seeded in petri dishes (diameter 15 cm) at a densityof 2×10⁶ cells in DMEM glutamax, 10% dialyzed FCS, and incubated at 37°C. over night. The following day cells were transfected withLipofectamine (Invitrogen, Karlsruhe, Germany) as recommended by themanufacturer, using linearised pcDNA3(−)-hmGlu7a (SspI). Aftertransfection cells were cultured in DMEM Glutamax Medium (Invitrogen),containing 10% dialyzed fetal calf serum (FCS; Invitrogen),antibiotic/antimycotic (Invitrogen) and 800 μg/ml Geneticin (G418).Single clones were isolated manually, tested for reduction of cellularcAMP (alpha screen) and subcloned by FACS. Single cell clones wereretested for cAMP reduction, and transfected with pcDNA3.1 (+) HygrorGLAST IRES Ga15 (SspI). The transfection was done identical asdescribed above. Cells were selected in DMEM Glutamax, 10% dialyzed FCS,antibiotic/antimycotic, 800 μg/ml G418 and 150 μg/ml Hygromycin. Singleclones were isolated by serial dilution and tested by FLIPR as describedabove.

e) mGlu1 and 5 Receptors

For the purpose of the present study, we generated by transfection acell line permanently expressing human mGlu5a and the rat glutamatetransporter rGLAST. Briefly, cells were transfected with Lipofectamine(Invitrogen, Karlsruhe, Germany), using linearised pcDNA3-hmGlu5a (ScaI)and pIRES-rGlast (SspI). After transfection the cells were cultured inDMEM Glutamax Medium (Invitrogen), containing 10% dialyzed fetal calfserum (FCS; Invitrogen), antibiotic/antimycotic, 800 μg/ml Geneticin(G418) and 150 μg/ml Hygromycin, and single clones were isolatedmanually. Identically, a cell line expressing mGlu1a was generated.Functional clones were selected using intracellular Ca²⁺ measurementswith a fluorescence imaging plate reader (FLIPR) under standardconditions as described above.

1. A compound of formula I

wherein X¹ is N or C-R¹ X² is N or C-R² X³ is N or C-R³ X⁴ is N or C-R⁴provided that none or one of X¹, X², X³ or X⁴ is N; Y¹ is N, C or C-R⁵Y² is N, C or C-R⁶ Y³ is N, C or C-R⁷ Y⁴ is N, C or C-R⁸ provided thatonly the moiety Y¹, Y², Y³ or Y⁴ to which Z is bound is C and furtherprovided that 0, or 1 of Y¹, Y², Y³ or Y⁴ is N; Z is CR^(Za)R^(Zb), O,S, S(O), S(O)₂ or NR^(Zc); R^(Za), R^(Zb) are independently of eachother selected from hydrogen, halogen and C₁-C₄-alkyl; R^(Zc) ishydrogen, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, orC₁-C₄-alkyl, which is unsubstituted or carries one radical selected fromC₁-C₄-alkoxy and NR^(Z1)R^(Z2); where R^(Z1) and R^(Z2) areindependently of each other selected from hydrogen, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl, C₁-C₄-alkyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, orR^(Z1) and R^(Z2) together with the nitrogen to which they are attachedform a 5- or 6-membered N-bound saturated heterocycle, which, inaddition to the nitrogen atom, may comprise a further heteroatom,selected from O, S and N, as ring member and which is unsubstituted orcarries 1, 2, 3 or 4 C₁-C₄-alkyl radicals; or R^(Zc) is a radicalS(O)₂R^(Z3) or a radical S(O)₂NR^(Z4)R^(Z5); where R^(Z3) isC₁-C₄-alkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, phenyl or benzyl, wherein thephenyl ring in the last two mentioned radicals itself is unsubstitutedor carries 1, 2, 3, 4 or 5 identical or different radicals selected fromhalogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy; R^(Z4) and R^(Z5) have one of the meanings given forR^(Z3) or R^(Z4) and R^(Z5) together with the nitrogen to which they areattached form a 5- or 6-membered N-bound saturated heterocycle, which,in addition to the nitrogen atom, may comprise a further heteroatom,selected from O, S and N as ring member and which is unsubstituted orcarries 1, 2, 3 or 4 C₁-C₄-alkyl radicals; Q is CH₂ or CH₂CH₂, where oneor two of the hydrogen atoms in CH₂ or CH₂CH₂ may be replaced byhalogen, C₁-C₄-alkyl or C₁-C₄-haloalkyl; R¹ is selected from hydrogen,halogen, C₁-C₆-alkyl, which is unsubstituted or carries one C₁-C₄-alkoxyradical, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₄-haloalkoxy,C₃-C₈-cycloalkyl, a radical NR^(1a)R^(1b), a radical CH₂NR^(1a)R^(1b),C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogenatoms and 0 or 1 heteroatoms, selected from O and S, as ring members,aryl, aryl-CH₂, aryloxy, hetaryl, hetaryloxy or hetaryl-CH₂, wherein thearyl, heterocyclyl and hetaryl rings ring in the last seven radicalsthemselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical ordifferent radicals R^(1c); R^(1a) is hydrogen, C₁-C₈-alkyl,C₁-C₈-haloalkyl, C₁-C₄-alkoxy-C₁-C₄-alkyl, C₃-C₈-cycloalkyl,C₁-C₈-alkylcarbonyl, C₁-C₈-alkoxycarbonyl,benzyl, phenyl or 5- or6-membered hetaryl, wherein the phenyl and hetaryl rings in the lastthree radicals itself are unsubstituted or carry 1, 2, 3, 4 or 5identical or different radicals R^(1c); R^(1b) is hydrogen orC₁-C₄-alkyl; or NR^(1a)R^(1b) is a 5- to 10-membered mono- or bicyclicN-bound saturated heterocycle, which, in addition to the nitrogen atom,may comprise a further heteroatom, selected from O, S and N as ringmember and which is unsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkylradicals; R^(1c) is selected from the group consisting of halogen, CN,OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy andC₁-C₄-haloalkoxy; R² is selected from hydrogen, halogen, C₁-C₆-alkyl,which is unsubstituted or carries one C₁-C₄alkoxy radical,C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C,₄-haloalkoxy, C₃-C₈-cycloalkyl, a 5-to 10-membered mono- or bicyclic N-bound saturated heterocycle, which,in addition to the nitrogen atom, may comprise a further heteroatom,selected from O, S and N as ring member and which is unsubstituted orcarries 1, 2, 3 or 4 C₁-C,₄-alkyl radicals, a radical CH₂NR^(la)R^(1b),C-bound 3- to 10-membered, saturated heterocyclyl having 1 or 2 nitrogenatoms and 0 or 1 heteroatoms, selected from O and S, as ring members,aryl, aryl-CH₂ aryloxy, hetaryl, hetaryloxy or hetaryl-CH₂ wherein thearyl, heterocyclyl and hetaryl rings ring in the last seven radicalsthemselves are unsubstituted or carry 1, 2, 3, 4 or 5 identical ordifferent radicals R^(1c) provided that R² is different from hydrogen,if X¹ is N or CH, further provided that R¹ is different from hydrogen,if X² is N; R³ and R⁴ are independently of each other, selected fromhydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₃-C₆-cycloalkyl,C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl, phenyl, C₁-C₄-haloalkoxy, aradical (CH₂)_(n)NR′R″, where R′ and R″ have one of the meanings givenfor R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4, or C-bound 3- to7-membered, saturated heterocyclyl having 1 or 2 nitrogen atoms and 0 or1 heteroatoms, selected from O and S, as ring members, where theheterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(6c), where R^(6c) has one of themeanings given for R^(1c); R² and R³ can form together with the carbonatoms, to which they are bound, a fused 5- to 6-membered ring, which isitself unsubstituted or carries 1, 2, 3 or 4 identical or differentradicals R^(23a); R^(23a) is selected from the group consisting ofhalogen, CN, OH, C₁-C₄-alkyl, C₃-C₆-cycloalkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy; R⁵ is hydrogen, halogen, CN,C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-alkoxy-C₁-C₄-alkyl,C₁-C₄-haloalkoxy, (CH₂)_(n)NR′R″, where R′ and R″ have one of themeanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or 4,or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ringmembers, where the heterocyclyl itself is unsubstituted or carries 1, 2,3, 4 or 5 identical or different radicals R^(5c), where R^(5c) has oneof the meanings given for R^(1c); R⁶, R⁷, R⁸ are, independently of eachother, selected from hydrogen, halogen, CN, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy, C₁-C₄-haloalkyoxy,C₁-C₄-alkoxy-C₁-C₄-alkyl, (CH₂)_(n)NR′R″, where R′ and R″ have one ofthe meanings given for R^(Z1) and R^(Z2) and wherein n is 0, 1, 2, 3 or4, or C-bound 3- to 7-membered, saturated heterocyclyl having 1 or 2nitrogen atoms and 0 or 1 heteroatoms, selected from O and S, as ringmembers, where the heterocyclyl itself is unsubstituted or carries 1, 2,3, 4 or 5 identical or different radicals R^(6c), where R^(6c) has oneof the meanings given for R^(1c); R^(a) is C₃-C₆-cycloalkyl,C₁-C₆-haloalkyl or C₁-C₆-alkyl, which is unsubstituted or carries oneradical selected from C₁-C₄-alkoxy, C₁-C₄-haloalkoxy and a radicalNR^(a1)R^(a2), where R^(a1) and R^(a2) are independently of each otherselected from hydrogen, C₁-C₄-alkyl, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl, a radicalNR^(a3)R^(a4) or a radical N═C(R^(a5))R^(a6), where R^(a3) and R^(a5)are independently of each other selected from hydrogen, C₁-C₄-alkyl,C₁-C₄haloalkyl, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl andC₁-C₄-alkoxy-C₁-C₄-alkyl; R^(a4) and R^(a6) are independently of eachother selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,C-bound 3- to 7-membered, saturated heterocyclyl, 3- to 7-membered,saturated heterocyclylmethyl, where heterocyclyl in the last twomentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms,selected from O and S, as ring members, aryl, aryl-CH₂, hetaryl andhetaryl-CH₂, wherein the heterocycicyl, aryl and hetaryl rings ring inthe last six radicals themselves are unsubstituted or carry 1, 2, 3, 4or 5 identical or different radicals R^(ac) where R^(ac) has one of themeanings given for R^(1c); the pharmaceutically acceptable salts; orN-oxides thereof.
 2. The compound of claim 1, wherein X² is CR², whereinR² is phenyl, benzyl or phenoxy, wherein the phenyl ring in the lastthree radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c).
 3. The compound of claim 1,wherein X² is CR², wherein R² is branched C₃-C₆-alkyl, C₁-C₆-haloalkylor C₃-C₆-cycloalkyl.
 4. The compound of claim 1, wherein X² is CR²,wherein R² is a 5-to 10-memebered mono- or bicyclic N-bound saturatedheterocycle, which in addition to the nitrogen atom, may comprise afuther heteroatom , selected from O, S and N as ring member and which isunsubstituted or carries 1, 2, 3 or 4 C₁-C₄-alkyl radicals, or C-bound3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atomsand 0 or 1 heteroatoms, selected from O and S, as ring members, wherethe heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(2c).
 5. The compound of claim 1,wherein X¹ is CH.
 6. The compound of claim 1, wherein X¹ is N.
 7. Thecompound of claim 1, wherein X² is CH or N and X¹ is CR¹, where R¹ isdifferent from hydrogen.
 8. The compound of claim 1, wherein R¹ isbranched C₃-C₆-alkyl, C₁-C₆-haloalkyl or C₃-C₆-cycloalkyl.
 9. Thecompound of claim 1, wherein R¹ is a radical NR^(1a)R^(1b) or C -bound3- to 7-membered, saturated heterocyclyl having 1 or 2 nitrogen atomsand 0 or 1 heteroatoms, selected from O and S, as ring members, wherethe heterocyclyl itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c).
 10. The compound of claim 1,wherein R¹ is phenyl, benzyl or phenoxy, wherein the phenyl ring in thelast three radicals itself is unsubstituted or carries 1, 2, 3, 4 or 5identical or different radicals R^(1c).
 11. The compound of claim 1,wherein Z is O or NH.
 12. The compound of claim 1, wherein X³ is CR³,wherein R³ is hydrogen, chlorine, fluorine, methyl, methoxy ortrifluoromethyl.
 13. The compound of claim 1, wherein X⁴ is CR⁴, whereinR⁴ is hydrogen, chlorine, fluorine, methyl, methoxy or trifluoromethyl.14. The compound of claim 1, wherein Y¹ is CR⁵, wherein R⁵ is hydrogen.15. The compound of claim 1, wherein R^(a) is C₃-C₆-cycloalkyl orC₂-C₆-alkyl which carries one radical selected from C₁-C₄-alkoxy,C₁-C₄-haloalkoxy and a radical NR^(a1)R^(a2), where R^(a1) and R^(a2)are independently selected from hydrogen and C₁-C₄-alkyl.
 16. Thecompound of claim 1, wherein R^(a) is a radical NR^(a3)R^(a4), whereR^(a3) is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl and C₁-C₄-alkoxy-C₁-C₄-alkyl;and R^(a4) is selected from hydrogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₃-C₆-cycloalkyl, C₃-C₆-cycloalkylmethyl, C₁-C₄-alkoxy-C₁-C₄-alkyl,C-bound 3 to 7 membered, saturated heterocyclyl, 3- to 7-membered,saturated heterocyclylmethyl, where heterocyclyl in the last twomentioned radicals has 1 or 2 nitrogen atoms and 0 or 1 heteroatoms,selected from O and S, as ring members, aryl, aryl-CH₂, hetaryl andhetaryl-CH₂, wherein the heterocycicyl, aryl and hetaryl rings ring inthe last six radicals themselves are unsubstituted or carry 1, 2, 3, 4or 5 identical or different radicals R^(ac), where R^(ac) has one of themeanings given for R^(1c).
 17. The compound of claim 1, wherein Q isCH₂.
 18. The compound of claim 1, wherein Q is CH₂CH₂.
 19. The compoundof claim 1, wherein the one of Y², Y³ and Y⁴, to which Z is bound, is Cwhile the others are CH.
 20. The compound of claim 1 of the formula Ia

wherein X¹, Z, Q, R², R³, R⁴, R⁵ and R^(a) are as defined above.
 21. Thecompound of claim 1 of the formula Ib

wherein X¹, Z, Q, R², R³, R⁴, R⁵ and R^(a) are as defined above.
 22. Thecompound of claim 1 of the formula Ic

wherein X¹, Z, Q, R², R³, R⁴, R⁵ and R^(a) are as defined above.
 23. Thecompound of claim 20, wherein X¹ is CH.
 24. The compound of claim 20,wherein Q is CH₂.
 25. The compound of claim 20, wherein Q is CH₂CH₂. 26.A pharmaceutical composition comprising a carrier and a compound ofclaim
 1. 27. The compound of claim 1, selected from the group consistingof: 2-butyl-5-(4-phenylpyridin-3-ylamino)isoindolin-1-one;2-butyl-5-(5-phenylpyridin-3-ylamino)isoindolin-1-one;2-butyl-5-(4-phenylpyridin-3-yloxy)isoindolin-1-one;2-butyl-7-chloro-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one;2-butyl-5- { [5-(piperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindo1-1-one; 2-butyl-5- {[2-chloro-5-(piperazin-1-yl)pyridin-3-yl] amino}-2,3-dihydro-1H-isoindo1-1-one;2-butyl-5-[(5-chloropyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one;2-butyl-5- { [5-(morpholin-4-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindo1-1-one; 2-butyl-5- {[2-chloro-5-(4-methylpiperazin-1-yl)pyridin-3-yl] amino} -2,3-dihydro-1H-isoindol-1-one; 2-butyl-5- { [5-(4-methylpiperazin-1-yl)pyridin-3-yl]amino}-2,3-dihydro-1H-isoindo1-1-one;2-butyl-5-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-one;2-butyl-4-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-onetrifluoroacetate;2-butyl-5-[(5-phenylpyridin-3-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-onetrifluoroacetate;2-butyl-6-[(5-phenylpyridin-3-yl)oxy]-3,4-dihydroisoquinolin-1(2H)-onetrifluoroacetate;2-butyl-6-[(5-phenylpyridin-3-yl)oxy]-2,3-dihydro-1H-isoindol-1-onetrifluoroacetate;2-butyl-5-(6-phenyl-pyrazin-2-ylamino)-2,3-dihydro-isoindo1-1-one;2-butyl-5-(quinolin-3-ylamino)-2,3-dihydro-1H-isoindo1-1-one;2-butyl-5-(quinoxalin-2-ylamino)-2,3-dihydro-1H-isoindo1-1-one;2-(2-methoxyethyl)-5-[(5-phenylpyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one;2-butyl-5-[(2-chloropyridin-3-yl)amino]-2,3-dihydro-1H-isoindol-1-one;2-butyl-5- { [2-chloro-5-(piperazin-1-yl)pyridin-3-yl]oxy}-3,4-dihydroisoquinolin-1(2H)-one; 2-butyl-5- {[2-chloro-5-(4-methylpiperazin-1-yl)pyridin-3-yl] oxy}-3,4-dihydroisoquinolin-1(2H)-one; and2-butyl-5-[(5-phenylpyridin-3-yl)methyl]-2,3-dihydro-1H-isoindol-1-one.28. A compound that is2-butyl-5-(5-phenylpyridin-3-yl)-2,3-dihydro-1H-isoindo1-1-one.
 29. Amethod for treating, controlling, ameliorating, or reducing the risk ofa medical disorder that responds to influencing by mGlu2 receptorantagonists or agonists, wherein the disorder is selected from the groupconsisting of anxiety, schizophrenia and epilepsy, the method comprisingadministering an effective amount of at least one compound of claim 1 toa host in need thereof.
 30. The method according to claim 29 wherein thedisorder is anxiety.
 31. The method according to claim 29 wherein thedisorder is schizophrenia.
 32. The method according to claim 29 whereinthe disorder is epilepsy.